KOLLIPHOR TPGS

KOLLIPHOR TPGS

KOLLIPHOR TPGS (VITAMIN E TPGS)

CAS No. : 9002-96-4

 

Synonyms:

VITAMIN E TPGS; vitamin e tpgs; Vitamin E Polyethylene Glycol Succinate; D-α-Tocopherol polyethylene glycol succinate; TPGS; Vitamin E polyethylene glycol succinate; Vitamin E-TPGS; kolliphor tpgs; kolifor tpgs; e vitamini; D-α-Tocopherol polyethylene glycol 1000 succinate; DL-A-TOCOPHEROL POLYETHYLENE GLYCOL SUCCINATE; DL-ALPHA-TOCOPHEROL POLYETHYLENE GLYCOL SUCCINATE; d-alpha-tocopheryl polyethylene glycol succinate; alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2h-1-benzopyran-6-yl)oxy)-1,4-dioxobutanol poly(ethylene glycol) succinate; tocofersolan; tocopherosolan; 2-ethanediyl),.alpha.-[4-[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzoPoly(oxy-1; 4-dioxobutyl)-omega-hydroxy–trimethyltridecyl)-2h-1-benzopyran-6-yl)oxy)-; D-alpha-Tocopheryl polyethylene glycol succinate; Tocofersolan; Vitamin E-TPGS; Vitamin E Polyethylene Glycol Succinate; Cyclosporine TPGS; alpha-Tocopheryl poly(ethylene glycol) 1000 succinate, D-; alpha-Tocopheryl poly(ethylene glycol)1000 succinate, d-; D 1T; d-alpha-Tocopheryl poly(ethylene glycol) 1000 succinate; EASTMAN Vitamin E TPGS; Tocofersolan; Tocofersolan [INN]; Tocofersolano; Tocofersolano [INN-Spanish]; Tocofersolanum; Tocofersolanum [INN-Latin]; Tocophersolan; Tocopheryl polyethylene glycol 1000 succinate; TPGS; UNII-O03S90U1F2; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl)-omega-hydroxy-, (2R-(2R*(4R*,8R*)))-; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl)-omega-hydroxy-, (2R-(2R*(4R*,8R*)))-; Tocophersolan; TPGS; Tocofersolan; Vitamin E TPGS; Tocophersolan [USAN]; Tocofersolano; Tocofersolanum; Tocofersolan (INN); Tocofersolan [INN]; Tocophersolan (USAN); (+)-alpha-Tocopheryl polyethylene glycol 1000 succinate; Tocopheryl polyethylene glycol 1000 succinate; alpha-Tocopheryl polyethylene glycol 1000 succinate; d-alpha-Tocopheryl poly(ethylene glycol) 1000 succinate; D 1T; Tocofersolan, INN; Tocophersolan, USAN; alpha-tocopheryl polyethylene glycol succinate; EASTMAN Vitamin E TPGS; Tocofersolanum [INN-Latin]; Tocofersolano [INN-Spanish]; 30999-06-5; Mono-(2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-6-chromanyl) succinate polyethylene glycol monoester; UNII-O03S90U1F2; SCHEMBL3139787; Aquasol E Tpgs Liquid 77iu/Ml; CTK8A5451; O03S90U1F2; BCP11679; AKOS015967005; 2-hydroxyethyl 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2h-chromen-6-yl succinate; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl-omega-hydroxy-; LS-184083; FT-0675259; NS00014159; D06174; Q172409; D-alpha-Tocopheryl poly(ethylene glycol)1000 succinate; alpha-Tocopheryl poly(ethylene glycol) 1000 succinate, D-; alpha-Tocopheryl poly(ethylene glycol)1000 succinate, d-; 1-(2-hydroxyethyl) 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-1-benzopyran-6-yl butanedioate; D08CVC;D-(c) paragraph sign-Tocopherol polyethylene glycol 1000 succinate; TPGS; Vitamin E-TPGS; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl)-omega-hydroxy-, (2R-(2R*(4R*,8R*)))-; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl)-omega-hydroxy-; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl)-omega-hydroxy-, (2R-(2R*(4R*,8R*)))-; VITAMIN E TPGS; vitamin e tpgs; Vitamin E Polyethylene Glycol Succinate; D-α-Tocopherol polyethylene glycol succinate; TPGS; Vitamin E polyethylene glycol succinate; Vitamin E-TPGS; kolliphor tpgs; kolifor tpgs; e vitamini; D-α-Tocopherol polyethylene glycol 1000 succinate; DL-A-TOCOPHEROL POLYETHYLENE GLYCOL SUCCINATE; DL-ALPHA-TOCOPHEROL POLYETHYLENE GLYCOL SUCCINATE; d-alpha-tocopheryl polyethylene glycol succinate; alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2h-1-benzopyran-6-yl)oxy)-1,4-dioxobutanol poly(ethylene glycol) succinate; tocofersolan; tocopherosolan; 2-ethanediyl),.alpha.-[4-[[3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzoPoly(oxy-1; 4-dioxobutyl)-omega-hydroxy–trimethyltridecyl)-2h-1-benzopyran-6-yl)oxy)-; D-alpha-Tocopheryl polyethylene glycol succinate; Tocofersolan; Vitamin E-TPGS; Vitamin E Polyethylene Glycol Succinate; Cyclosporine TPGS; alpha-Tocopheryl poly(ethylene glycol) 1000 succinate, D-; alpha-Tocopheryl poly(ethylene glycol)1000 succinate, d-; D 1T; d-alpha-Tocopheryl poly(ethylene glycol) 1000 succinate; EASTMAN Vitamin E TPGS; Tocofersolan; Tocofersolan [INN]; Tocofersolano; Tocofersolano [INN-Spanish]; Tocofersolanum; Tocofersolanum [INN-Latin]; Tocophersolan; Tocopheryl polyethylene glycol 1000 succinate; TPGS; UNII-O03S90U1F2; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl)-omega-hydroxy-, (2R-(2R*(4R*,8R*)))-; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl)-omega-hydroxy-, (2R-(2R*(4R*,8R*)))-; Tocophersolan; TPGS; Tocofersolan; Vitamin E TPGS; Tocophersolan [USAN]; Tocofersolano; Tocofersolanum; Tocofersolan (INN); Tocofersolan [INN]; Tocophersolan (USAN); (+)-alpha-Tocopheryl polyethylene glycol 1000 succinate; Tocopheryl polyethylene glycol 1000 succinate; alpha-Tocopheryl polyethylene glycol 1000 succinate; d-alpha-Tocopheryl poly(ethylene glycol) 1000 succinate; D 1T; Tocofersolan, INN; Tocophersolan, USAN; alpha-tocopheryl polyethylene glycol succinate; EASTMAN Vitamin E TPGS; Tocofersolanum [INN-Latin]; Tocofersolano [INN-Spanish]; 30999-06-5; Mono-(2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-6-chromanyl) succinate polyethylene glycol monoester; UNII-O03S90U1F2; SCHEMBL3139787; Aquasol E Tpgs Liquid 77iu/Ml; CTK8A5451; O03S90U1F2; BCP11679; AKOS015967005; 2-hydroxyethyl 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2h-chromen-6-yl succinate; Poly(oxy-1,2-ethanediyl), alpha-(4-((3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl)oxy)-1,4-dioxobutyl-omega-hydroxy-; LS-184083; FT-0675259; NS00014159; D06174; Q172409; D-alpha-Tocopheryl poly(ethylene glycol)1000 succinate; alpha-Tocopheryl poly(ethylene glycol) 1000 succinate, D-; alpha-Tocopheryl poly(ethylene glycol)1000 succinate, d-; 1-(2-hydroxyethyl) 2,5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydro-2H-1-benzopyran-6-yl butanedioate

 

 

Kolliphor TPGS

 

 

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS): Solution for insolubility

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) – D-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) – is a water-soluble derivative of vitamin E that can directly enhance the bioavailability of poorly soluble actives. TPGS is commonly used in pharmaceutical and nutraceutical formulations.

Key Features of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)

Based on natural-source vitamin E from BASF

Conforms to USP-NF monograph “Vitamin E Polyethylene Glycol Succinate”

Produced according to IPEC-PQG GMP guidelines

No chlorinated solvents used

Detailed technical and regulatory information available

Enhanced delivery of life-saving drugs

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) directly increases the bioavailability and delivery of poorly soluble drugs.

TPGS can be used in oral, topical and parenteral dosage forms.

It is also used in dietary supplements, cosmetic applications and food.

Key benefits for customers

Cognis is a leading supplier of natural-source vitamin E and pharma-grade excipients, and has considerable expertise in solubilizers.

Using its own vitamin E feedstocks, BASF guarantees consistent quality and a competitive, reliable supply of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS).

In accordance with stringent industry requirements, BASF maintains the highest manufacturing standards, with full supporting documentation.

TPGS from BASF offer high solubilisation effectiveness.

BASF offers a global sales network plus technical and regulatory support.

Applications of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS):

-Drug solubilizer

-Absorption enhancer

-Emulsifier

-Vehicle for lipid-based drug delivery

-Source of natural vitamin E

-Antioxidant

BASF will transfer the pharmaceutical production of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) (Speziol TPGS Pharma, vitamin E polyethylene glycol succinate), manufactured at the company’s Kankakee, Illinois (USA), site, to its Minden, Germany, facility. The transition is expected to be completed by the first quarter of 2014.

“Expanding the Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) manufacturing capacity at our Minden site is another example of BASF’s commitment to the pharmaceutical and dietary supplement market. The relocation creates a more centralized production facility, reduces complexity in the production setup, and provides room for future expansion,” said Dr. Thorsten Schmeller, Head of Global Marketing New Products at BASF’s Global Business Unit Pharma Ingredients & Services. The Minden site has manufactured active pharmaceutical ingredients (APIs) and excipients under cGMP for more than 70 years and is regularly inspected by the FDA and European health authorities. Schmeller: “Thanks to the ICH Q7 quality management standards at our Minden site, we will be able to offer a Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) grade that fulfills the requirements of an API.”

Commitment to a seamless transition

Until the production in Minden is fully operational, BASF will continue to manufacture Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) at the Kankakee site, which will fully support pharmaceutical and nutraceutical customers during the transition. “We have scheduled a generous supply overlap that we expect allows for a seamless transition,” added Schmeller. “Our projection also takes into account the appropriate qualification period required to transition products used in pharmaceutical applications.” Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) production at the Minden site is expected to start in the first quarter of 2013.

The Kankakee site remains an important production facility for BASF’s nutrition and health business. Besides food ingredients, the company manufactures ingredients for soaps, shampoos, detergents, coatings, inks and adhesives at the site.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) is a water-soluble derivative of vitamin E that can directly enhance the bioavailability of poorly soluble active substances. It is commonly used in pharmaceutical and nutritional formulations, but also in cosmetics. Additionally it has plasticizing effects that are very beneficial for emerging platform technologies in the pharmaceutical industry such as hot melt extrusion (HME).

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) is a water-soluble derivative of vitamin E that can directly improve the bioavailability of poorly soluble active substances.

BASF Global Business Unit Pharma Ingredients & Services Global Marketing New Products head Thorsten Schmeller said the relocation creates a centralized production facility, reducing complexity in the production setup, while providing room for future expansion.

The company said until the production in Minden is fully operational, it will continue to manufacture Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) at the Kankakee site.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) is commonly used in pharmaceutical and nutritional, as well as in cosmetic formulations.

The production of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) at the Minden site is likely to begin in the first quarter of 2013 with the completion scheduled to Q1, 2014.

 

 

D-ɑ-tocopheryl polyethylene glycol succinate (Vitamin E Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) or Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)) has been approved by FDA as a safe adjuvant and widely used in drug delivery systems. The biological and physicochemical properties of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) provide multiple advantages for its applications in drug delivery like high biocompatibility, enhancement of drug solubility, improvement of drug permeation and selective antitumor activity. Notably, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can inhibit the activity of ATP dependent P-glycoprotein and act as a potent excipient for overcoming multi-drug resistance (MDR) in tumor. In this review, we aim to discuss the recent advances of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) in drug delivery including Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based prodrugs, nitric oxide donor and polymers, and unmodified Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based formulations. These potential applications are focused on enhancing delivery efficiency as well as the therapeutic effect of agents, especially on overcoming MDR of tumors. It also demonstrates that the clinical translation of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based nanomedicines is still faced with many challenges, which requires more detailed study on Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) properties and based delivery system in the future.

Vitamin E has been identified as an essential factor for reproduction since 1922 1. With further investigation, it has been found with other functions involving antioxidant, anti-thrombolytic and other therapeutic effects 2, 3. However, the poor water solubility of vitamin E has greatly limited its application 4. Vitamin E d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (simply as Vitamin E Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) or Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)), synthesized by esterification of vitamin E succinate with poly(ethylene glycol) (PEG) 1000, is a water-soluble derivative of natural vitamin E 5. It has an amphiphilic structure comprising hydrophilic polar head portion and lipophilic alkyl tail. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can be functionalized as an excellent solubilizer, emulsifier, permeation and bioavailability enhancer of hydrophobic drugs 6. Meanwhile, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can act as an anticancer agent, which has been demonstrated to induce apoptogenic activity against many cancer types. It can target the mitochondria of cancer cells, resulting in the mitochondrial destabilisation for activation of mitochondrial mediators of apoptosis 7. Interestingly, it has been documented that Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can selectively induce apoptosis in tumor cells while exhibited nontoxicity to normal cells and tissues 8.

Multi-drug resistance (MDR) remains as a significant impediment to successful chemotherapy in clinical cancer treatment. What’s worse, decades of research has identified that this phenomenon exists in nearly every effective drug, even the newest therapeutic agents 9. Therefore, how to effectively reverse drug resistance plays a critical role in achieving satisfied therapeutic effect in cancer treatment. It has been demonstrated that various mechanisms are involved in MDR including decreased drug influx, increased drug efflux, changed drug metabolism and promoted anti-apoptotic mechanism 10. Among them, the drug efflux mediated by ATP-binding cassette transporter P-glycoprotein (ABCB1) is one of the most investigated and characterized mechanisms for MDR. P-glycoprotein (P-gp) has 12 transmembrane regions to bind hydrophobic substrate drugs and two ATP-binding sites to transport drug molecules 11. It can pump out P-gp substrate drugs to the extracellular space and thus decrease the intracellular drug accumulation. Over the past few decades, considerable efforts have been devoted to exploring P-gp inhibitors for overcoming MDR. Several nonionic surfactants such as Pluronic, Tweens, Span and Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) have been found with the ability to inhibit P-gp activity 12, 13. Though the exact mechanism of P-gp inhibition by these surfactants remains unclear, steric blocking of substrate binding 14, alteration of membrane fluidity 15 and inhibition of efflux pump ATPase 16, 17 have been proposed as the potential mechanisms. As a widely used adjuvant in drug delivery, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) has been shown as the most potent and commercially available P-gp inhibitor among these surfactants 18. As a membrane transporter of ATP-binding cassette family, P-gp can pump out the substrate drug via an ATP-dependent mechanism 19. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can target the mitochondria and cause its dysfunction, resulting in the depletion of intracellular ATP. The reduced ATP level can then influence the activity of P-gp and decrease the drug efflux to extracellular space 20. Besides, the hydrolysis of ATP by ATPase is critical for converting the P-gp transporter to an active conformational state for substrate drug efflux 16. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) itself cannot stimulate ATPase activity as it is not a substrate of P-gp, but can inhibit the substrate induced ATPase activity 21. In our previous works, we have demonstrated that Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can significantly enhance the intracellular accumulation and cytotoxicity of chemotherapeutics to drug resistant breast adenocarcinoma cells (MCF-7/ADR) and human ovarian cancer cells (A2780/T) 22-24.

Since Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) has been approved by the FDA as a safe pharmaceutical adjuvant, it has been extensively used in drug delivery systems as surfactant, solubilizer, stabilizer and P-gp inhibitor for enhancing bioavailability and reversing MDR. In our previous reviews 5, 6, we discussed Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) as a molecular biomaterial and its original application in drug delivery. In this review, we focused on the progress of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) in drug delivery in recent five years, which took advantages of the P-gp inhibiting ability and other basic properties. We summarized the applications of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based prodrugs, nitric oxide (NO) donor and polymers for overcoming MDR and delivering therapeutic agents. We also discussed the unmodified Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based formulations applied in reversing MDR, improving oral availability and enhancing drug permeation. We expect this review will give new inspiration for the application of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) in overcoming MDR and drug delivery.

 

 

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) as a surfactant

Poor water solubility and/or poor permeability remain as the major obstacles for therapeutic drugs to exert maximum activity. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can be applied as solubilizer, absorption and permeation enhancer, emulsifier as well as surface stabilizer in drug delivery. It has been widely used in fabricating nanodrugs or other formulations for many poorly water-soluble or permeable drugs, especially for biopharmaceutics classification system (BCS) class Ⅱ and Ⅳ drugs 5, 6. In addition, it has been reported that Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) exhibited strong enhancement on the secretion of chylomicrons at low concentration and enhanced the intestinal lymphatic transport 25, which would further improve drug absorption ability.

As a surfactant, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) shows outstanding capability to increase drug absorption through different biological barriers. For example, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) was used to fabricate repaglinide nanocrystals for enhancing saturation solubility and oral bioavailability up to 25.7-fold and 15.0-fold compared with free drug, respectively 26. In Ussing chambers transport studies, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can enhance drug permeation in colonic tissue 27. In addition, the influence of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) on the intestinal absorption ability of icariside Ⅱ was investigated in Caco-2 monolayer model and a four-site rat intestinal perfusion model. In Caco-2 monolayer model, the apparent permeability coefficients value of icariside Ⅱ was increased and the efflux ratio was remarkably reduced owing to the effect of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS). The four-site rat intestinal perfusion model investigation further showed significantly increased permeability of icariside Ⅱ in ileum and colon 28. Similar results were found in Caco-2 monolayer model with rhodamine123 (Rh123) in the presence of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) 29. Interestingly, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can also act as a pore-forming agent in the fabrication of nanoparticles with high drug encapsulation efficiency, small particle size and fast drug release 30. Besides, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can be used as emulsifier or surface stabilizer for the preparation of drug formulations as the hydrophobic portion can entrap hydrophobic drug and the hydrophilic part can stabilize the formulations.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) as a P-gp inhibitor for overcoming MDR

Drug resistance of cancer cells can restrict the therapeutic efficacy in chemotherapeutic treatment. As the ATP dependent membrane transporter, P-gp has been one of primary causes for MDR. It can pump out the P-gp substrate drugs to decrease intracellular drug accumulation, thus reducing the cytotoxic effect of chemotherapeutic drugs in drug resistant cancer treatment. Over the past decades, there have been continuous interests to combine P-gp substrate drugs with inhibitor or some polymer with P-gp inhibiting capability in formulations for overcoming MDR 31. Rh123, a P-gp substrate, is usually used as the model drug to study the intracellular retention of drug in MDR tumor cells. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can significantly increase the intracellular accumulation of Rh123 in drug-resistant tumor cells compared with free Rh123, which was evidenced from the flow cytometry and confocal microscope analysis 32. It seems that Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can effectively inhibit the activity of P-gp to overcome MDR.

Since the efflux transporter P-gp is ATP-dependent, the depletion of ATP plays a very important role in overcoming MDR. The MDR reversing effect of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) is mainly attributed to its dual actions, the inhibition of mitochondrial respiratory complex Ⅱ for shorting ATP supply and the suppression of substrate induced P-gp ATPase activity for blocking ATP utilization 20, 21, 33, 34.

Mitochondrial respiratory complex Ⅱ, also called succinate dehydrogenase, plays an important role in mitochondrial electron transport, which is an essential part in the tricarboxylic acid cycle as well as the mitochondrial respiratory chain 35. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can bind with mitochondrial respiratory complex Ⅱ and induce subsequent mitochondrial dysfunction, resulting in significant depletion of intracellular energy 20, 36. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can accumulate in mitochondria and inhibit the activity of complex Ⅱ, and consequently disrupt the electron transfer and activate calcium channel, which would result in the overload of calcium and ensuing dysfunction of mitochondria. Mitochondrial dysfunction is characterized by the dissipating effect on mitochondrial membrane potential, decreased ATP level and increased reactive oxygen species (ROS) generation 37. Furthermore, the mitochondrial targeting ability of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) may accelerate the mitochondrial dysfunction 32, 38. Substrate induced P-gp ATPase activity suppression is another mechanism for Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) to decrease drug efflux 21. ATPase activity can be stimulated by the binding of substrate to transmembrane regions of P-gp 39. Subsequently, ATP is transformed into adenosine diphosphate (ADP) for the energy supply of drug efflux. Unlike the classical P-gp inhibitor verapamil, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) is not a substrate of P-gp and shows no competitive inhibition effect of substrate binding. The steric blocking function of the binding site and/or allosteric modulation of P-gp appear to be the ATPase inhibition mechanism.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) as a selective anticancer agent for synergistic antitumor effects

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can induce apoptosis and exhibits selective cytotoxic effects against cancer cells, which can be combined with chemotherapeutic drugs for reducing side effect and increasing treatment efficiency. There is significant different response on normal immortalized breast cells and cancer cells after Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) treatment. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can trigger the apoptotic signaling pathways and induce G1/S cell cycle arrest in breast cancer cells MCF-7 and MDA-MB-231, but no remarkable effect on non-tumorigenic cells MCF-10A and MCF-12F 40. Coincidentally, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can induce apoptosis on T cell acute lymphocytic leukemia Jurkat clone E6-1 cells, but not on human peripheral blood lymphocytes. The apoptosis was evidenced by increased nuclear DNA fragmentation, enhanced cell cycle arrest and reduced mitochondrial membrane potential 41. The selective apoptosis mechanisms of cancer cells mediated by Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) are complicated and can be listed as follows:

 

 

ROS inducer

Similar to α-tocopheryl succinate (α-TOS), Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can induce cancer cell apoptosis through the destruction and inhibition of mitochondrial respiratory complex Ⅱ 33, 41. The subsequent electron transfer chain disruption can promote ROS generation 20. The escalated intracellular ROS, a mediator of apoptosis, can induce DNA damage and the oxidation of lipid, protein and enzyme, leading to cell destruction 42. Besides, it has been demonstrated that ROS-mediated apoptosis mechanism was correlated with the selective anticancer activity as tumor cells could be more sensitive to ROS than normal cells 43-45. Compared with TOS, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) exhibited enhanced ROS generation capability 46.

Downregulation of anti-apoptotic proteins

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can inhibit the phosphorylation of protein kinase B (PKB or AKT) and then downregulate the anti-apoptotic proteins Survivin and Bcl-2, which can induce the activation of caspase-3 and -7 for caspase-dependent programmed cell death 40. Concurrently, caspase-independent programmed cell death and G1/S phase cell cycle arrest also occurred 40, 41. Survivin and Bcl-2 are usually overexpressed in most cancer cells while remarkably reduced in normal cells 47. This may be the main reason for the selective cytotoxicity of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS).

DNA damage

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can induce both caspase-dependent and caspase-independent DNA damage. This kind of DNA damage was observed in androgen receptor positive (AR+) LNCaP cells but not in AR- DU145 and PC3 cells, which was related to the cellular microenvironment 48.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX conjugate

Doxorubicin (DOX) is a P-gp substrate and broad spectrum anticancer drug. However, the acquired drug resistance of DOX is an obstacle to its clinical applications in the progress of cancer therapy. Bao et al. 23 developed a pH-sensitive Schiff base-linked prodrug, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-CH=N-DOX (also called TD), by conjugating DOX with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) for overcoming MDR. This prodrug can self-assemble into stable micelles in physiological condition and realize in vivo tumor targeting and long blood circulation by introducing a PEGylated lipid. It was the first time to provide a “molecular economical” way to combat tumor as the system combined the tumor targeting from the integrin receptor ligand peptide cyclic RGD (cRGD), long circulation property from PEGylated lipid, overcoming MDR from the material Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and stimuli-responsive release from Schiff based linker. The formulated hybrid micelles showed pH-sensitive drug release profile and obvious particles size change in pH 5.0 buffer which simulated the endo/lysosomal acidic environment. It also demonstrated increased DOX uptake by flow cytometry and confocal microscope analysis, and enhanced retention through in vivo pharmacokinetics compared with free drug. DOX exhibited good retention in drug sensitive MCF-7 cells during incubation. On the contrary, free drug showed much low DOX content and remarkably reduced retention in MCF-7/ADR cells even with extended incubation time. Both the P-gp inhibitors of verapamil and Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can increase the drug accumulation in MCF-7/ADR cells. The prodrug micelles achieved the similar drug uptake and retention trend with the admixture of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and DOX in MCF-7/ADR cells. It seems that the rapidly dissociated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) from the internalized micelles can inhibit the P-gp activity and retain DOX for subsequent cytotoxicity against MDR tumors. The enhanced cytotoxicity and apoptosis was induced by the hybrid micelles in MCF-7/ADR cells compared with free DOX as the half-maximal inhibitory concentrations (IC50) of hybrid micelles was 95-fold lower than that of free drug after 72 h incubation. The mechanism of antitumor efficacy was further investigated through the analysis of intracellular ROS production, change of mitochondrial membrane potential (ΔΨm) and intracellular ATP level (Figure ​Figure22B). The accumulation of ROS, decreased mitochondrial membrane potential and decreased ATP generation from the hybrid micelles may contribute to the P-gp inhibition by Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) with cutting off the energy supply from the ‘cellular power plants’ of mitochondria. The prodrug exhibited significant growth inhibition on MCF-7/ADR tumor (Figure ​Figure22C) and also tumor growth/metastasis inhibition on murine melanoma B16F10 and hepatocarcinoma H22 with cRGD decorated on the hybrid micelles. It provided a safe and simple prodrug platform to relieve the burden from delivery system and improve the therapeutic efficiency of nanomedicine through the rational design of prodrug for effective cancer treatment.

Some other Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX prodrugs were also designed and constructed 55-57. Feng’s group 55 developed Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX prodrug by directly conjugating succinic anhydride modified Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) with DOX. The prodrug showed improved cell uptake and cytotoxicity. Compared with free drug, 4.5- and 24-fold of half-life (t1/2) and area under curve (AUC) were found in Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX prodrug, respectively. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX-folic acid conjugate (Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX-FOL) was further introduced for targeted chemotherapy with higher therapeutic effects and fewer side effects 56. Moreover, the prodrug of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX can also be applied to package drug for combinational therapy. Hou et al. 57 constructed an acid-sensitive Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX prodrug by firstly synthesizing a pH-sensitive cis-aconitic anhydride-modified DOX and then conjugating with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS). The prodrug can self-assemble into nanoparticles. Photosensitizer chlorin e6 (Ce6) was loaded in this Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-DOX prodrug nanoparticles for near-infrared fluorescence imaging and combination of chemotherapy and photodynamic therapy against tumor. The nanoparticles exhibited pH-responsive DOX and Ce6 release characteristics, which was caused by the acid-sensitive linker between Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and DOX. It also demonstrated synergistic effects on cell uptake, cancer cell apoptosis and significant growth suppression in non-small cell lung cancer (A549).

 

 

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-PTX conjugate

Paclitaxel (PTX) is a BCS class Ⅳ drug with poor solubility and permeability as well as a P-gp substrate, which hinders the effective drug delivery and MDR tumor therapy. Zhang’s group 58 synthesized a redox-sensitive prodrug Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-SS-PTX, which could be rapidly dissociated in intracellular redox environment (high GSH concentration) to release PTX for cytotoxicity against tumor and Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) active ingredient for P-gp inhibition. The prodrug can self-assemble to stable micelles and realize the passive tumor targeting through the enhanced permeation and retention (EPR) effect. Compared with non-responsive ester bond conjugated PTX prodrug Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-CC-PTX, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-SS-PTX exhibited better stability and in vitro sustained drug release triggered by intracellular reductive environment. The increased stability of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-SS-PTX micelles may be attributed to the soft sulfurs linker between Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and PTX in comparison to the only two carbon linker of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-CC-PTX. Compared with the clinical formulation of Taxol® and Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-CC-PTX, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-SS-PTX micelles exhibited increased intracellular PTX accumulation for drug-resistant A2780/T cells, which may be caused by the rapid dissociated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) from the redox-sensitive prodrug. Rh123 was used as a model drug of P-gp substrate to evaluate the drug retention in MDR tumor. When the cells treated with verapamil or prodrugs, Rh123 fluorescence intensity was increased compared with free Rh123. In particular, much higher fluorescence intensity was exhibited in Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-SS-PTX compared with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-CC-PTX, which further confirmed the P-gp inhibition property from dissociated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS). As expected, this functional prodrug micelle increased the cytotoxicity of PTX in A2780/T cells. Compared with the uncleavable Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-CC-PTX prodrug and Taxol®, the stimuli-responsive prodrug reduced the IC50 and increased the apoptosis/necrosis of MDR tumor. In vivo evaluation further demonstrated the potential of this prodrug micelle on cancer treatment as the increased AUC, extended t1/2, enhanced drug distribution in tumor and significant tumor growth inhibition with reduced side effects.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-cisplatin conjugate

Cisplatin is widely used in testicular, ovarian, cervical, head and neck, and non-small-cell lung cancers. However, the clinical application is limited for low solubility, nephrotoxicity, severe peripheral neurotoxicity, inherent and acquired drug resistance 59. Feng’s group 60 developed Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-cisplatin prodrug to improve the water-solubility and reduce the neurotoxicity of cisplatin. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-cisplatin can self-assemble to micelles with high drug loading capability. The higher cell uptake and cytotoxicity against HepG2 hepatocarcinoma cells were found in Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-cisplatin prodrug compared with free drug. The prodrug micelles also showed significant neuroprotective effects with higher IC50 value for the SH-SY5Y neuroblast-like cells in comparison to free cisplatin. In addition, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) is a powerful anticancer agent when dealing with breast cancer with high level of human epidermal growth factor receptor 2 (HER2) expression 61. It may be related to the inhibition effect of mitochondrial respiratory complex Ⅱ and the ensuing ROS generation, resulting in cell apoptosis via the HER2 receptor tyrosine kinase signaling pathway 33. Mi and coworkers 62 developed a targeted delivery system of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-cisplatin prodrug nanoparticles for the co-delivery of cisplatin, docetaxel (DTX) and Herceptin for good tumor inhibition in HER2 overexpressed breast cancers. Poly(lactic acid) (PLA)-Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS), Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-COOH and Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-cisplatin were mixed to fabricate nanoparticles for the multimodality treatment of breast cancer. The multidrug-loaded nanoparticles exhibited much lower IC50 value for SK-BR-3 cells with high expression of HER2 compared with the admixture of free drugs.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-5-FU conjugate

Liu’s group 63, 64 developed multifunctional nanoparticles for co-delivery of hydrophobic drug PTX and hydrophilic drug 5-fluorouracil (5-FU) to overcome MDR. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-5-FU was synthesized by simply conjugating succinoylated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) with 5-FU. The nanoparticles, composed of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-5-FU prodrug and PTX, showed enhanced cytotoxicity against MDR tumor compared with individual agent treatment 64. They further developed nanoemulsions with PTX-Vitamin E and Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)-5-FU prodrug. The nanoemulsions with drugs co-delivery exhibited synergistic effect of overcoming PTX resistance in human epidermal carcinoma cell line KB-8-5 63. The effective anticancer activity was resulted from the P-gp inhibition effect of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and the synergistic effect of PTX and 5-FU which can simultaneously target diverse signaling pathways for cancer killing.

Targeting ligand conjugated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)

RGD has been applied as a potential targeting ligand in cancer treatment for tumors with αvβ3 integrin receptors overexpression. Li’s group 112 formulated PTX and Survivin shRNA co-loaded targeted nanoparticles by mixing Pluronic P85-polyethyleneimine, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and iRGD-Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) for overcoming drug resistance (Figure ​Figure55A). The nanoparticles exhibited increased cell uptake, RNA interference effect and cytotoxicity both on A549 and A549/T cells. It was further evidenced that the targeted nanoparticles showed significant antitumor effects from the co-delivery system as comparison to Taxol®. RGD-conjugated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) was also used to prepare the targeted micelles by mixing with vitamin E succinate (VES)-grafted-chitosan oligosaccharide, which exhibited good growth inhibition on human glioblastoma tumor (U87MG) 113. tLyp-1 peptide has high affinity to neuropilin-1 receptor (NRP-1). It can be also used as a targeting peptide to decorate on the surface of nanoparticles as overexpressed NRP-1 on tumor and angiogenesis cells. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) was first conjugated with the tLyP-1 peptide and then mixed with PLA-Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and Ce6-conjugated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) to fabricate DOX loaded nanoparticles via a nanoprecipitation method. The resultant nanoparticles can enhance the vascular extravasation and improve the penetration and accumulation of drugs in tumor for synergistic antitumor effects of combinational chemo-photodynamic therapy (Figure ​Figure55B) 114. In addition, a kind of theranostic micelles of transferrin conjugated Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) was applied for targeted co-delivery of DTX and gold clusters for simultaneous cancer imaging and therapy. The micelles exhibited enhanced cytotoxicity with 71.7-fold and 4.7-fold lower IC50 values in MDA-MB-231-luc breast cancer cells with transferrin receptors overexpression as comparison to Taxotere® and non-targeted micelles, respectively. The in vivo imaging and antitumor efficacy were further evidenced in tumor-bearing mice 115.

Unmodified Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based formulations

According to the basic properties mentioned above, unmodified Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can be used as a multifunctional material in drug delivery system. These functions can be summarized as overcoming MDR, improving oral drug bioavailability and promoting drug permeation.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based formulations to overcome MDR

Scientific investigations have validated that Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can be employed as the drug carrier and P-gp inhibitor in fabricating nanodrugs for MDR reversal in cancer treatment (Table ​Table33). Gao et al. 120 developed the Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) stabilized PTX nanosuspensions, which exhibited 2-fold median lethal dose (LD50) of acute toxicity and improved pharmacokinetics compared to that of the marketed injection. The nanosuspensions were further evaluated on P-gp overexpressed H460 human lung cancer cells (H460/RT) with significantly high cytotoxicity and 5-fold increase on tumor inhibitory rate compared with the mixed solution of PTX and Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) after i.v. administration 121. Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) was also used to prepare PTX nanoemulsions for overcoming drug resistance in MCF-7/ADR cells. The nanoemulsions exhibited significant P-gp inhibition and 94% tumor inhibitory rate (Figure ​Figure66A) 18.

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based formulations to promote drug permeation

Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can improve drug permeation across physiological barriers such as skin or cornea. It can be applied to construct many formulations for transdermal drug delivery and the therapy of eye diseases.

 

 

The ibuprofen supersaturated solution with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and hydroxypropyl methylcellulose (HPMC) exhibited higher permeation rate and longer onset of crystallization time compared with other solubilizer/polymer systems, which may be applicable in transdermal drug delivery systems 155. Following this work, the Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS)/HPMC nanosuspensions improved the permeability of ibuprofen with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) as solubilizer through the Skin-A Case Study 156. Moreover, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) nanoemulsion based nanogels were formed for topical delivery of amphotericin B to treat cutaneous fungal infections. The nanogels exhibited 3.9-fold higher skin deposition through porcine ear skin and 2.0-fold higher antifungal activity against Aspergillus niger and Candida albicans compared with the marketed topical formulation. The nanogels can penetrate into the deeper layers of skin 157. A topical formulation of griseofulvin, an antifungal agent, was prepared in the Carbopol (980 NF) base with the combination of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) as the penetration enhancer. The formulation exhibited enhanced drug permeation and retention in skin and showed great potential as the convenient alternative for the treatment of superficial fungal infection 158.

In parallel with transdermal drug delivery, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) was applied to promote drug translocation in cornea. Poor water solubility of drugs would limit the penetration and restrict pharmacological effects for eye diseases. Cholkar et al. 159 prepared dexamethasone-loaded micelles with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and octoxynol-40 (Oc-40) (weight ratio 4.5:2.0). The mixed polymers exhibited lower CMC (0.012 wt%) compared with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) (0.025 wt%) and Oc-40 (0.107 wt%). The safety of formulations was evidenced from the cytotoxicity on rabbit primary corneal epithelial cells. Rapamycin-loaded micelles were also prepared with Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) and Oc-40, which exhibited good tolerance as the low in vitro cytotoxicity on human retinal pigment epithelial and rabbit primary corneal epithelial cells. The micelles also exhibited feasibility in clinical application as the negligible drug partition into vitreous humor but very high drug level in targeted site of retina-choroid 160. Moreover, in situ CUR gels were prepared by dispersing an ion-sensitive Pluronic P123/Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) mixed micelles in gellan gum solution. The gels exhibited better corneal penetration and longer ocular retention compared with CUR solution 161.

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Conclusions and perspectives

In this review, we summarized the properties and recent progress of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) in drug delivery. The merits of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) for drug delivery are listed here as following ones. (i) Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) has been approved by FDA as a safe pharmaceutical adjuvant with high biocompatibility. (ii) Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can serve as an effective P-gp inhibitor for overcoming MDR. (iii) Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) itself can act as an anticancer agent with selective toxicity to tumor cells. (iv) Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can be easily combined with nanotechnology to develop nanomedicines, which has been shown as a promising strategy in cancer treatment with increased solubility and stability of therapeutic agents, improved PK/PD, enhanced treatment efficiency and reduced side effects. Here we discussed many examples to use Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based nanomedicines including Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based prodrugs, NO donor and polymers, and unmodified Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based formulations, which took advantages of the properties of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) in drug delivery, especially the potent effect to overcome MDR. These examples clearly illustrated the potential and promising applications of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) for overcoming MDR, improving oral bioavailability, promoting drug permeation and other functions.

P-gp inhibition has been widely accepted as the major mechanism of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) to overcome MDR. Though mitochondria dependent P-gp pump inhibition has been well characterized, there is little cue about the exact mechanism of ATPase inhibition by Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS). It remains unclear whether the ATPase inhibition is achieved by steric blocking of substrate binding, the direct interaction of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) with P-gp nucleotide binding domains or indirectly influencing P-gp function via an allosteric modulation 34. Besides, Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) may not work with the drug resistance acquired from tumor heterogenicity during tumor progression. It has been reported that Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can prevent tumor invasion and metastasis. The underlying mechanisms are unknown and still need to be investigated for more comprehensive application of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) in tumor metastasis. Furthermore, the impact of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) on immune system requires to be studied for the reason that Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) can be used as an adjuvant in vaccine development for cancer immunotherapy. As to Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based formulations, the limitations to realize the precise stimuli-responsive property and deep penetration of nanoformulations in tumor microenvironment still remain as obstacles for the widespread application of these nanomedicines. More effective strategies should be exploited to enhance the targeted delivery efficiency, achieve the controlled drug release and increase the penetration of therapeutics in tumor. Clinical translation is the ultimate goal for the development of nanomedicines, which should be focused on simple structure with multifunctional properties. Taking advantage of the biocompatibility and multiple functions of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS), Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based nanomedicines may be promising for the property as “molecular economy” in pharmaceutics. However, the preparation of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) nanomedicines is still in laboratory scale and the progress on developing novel nanomedicines is relatively slow, which hinders the successful clinical translation of Kolliphor TPGS (VITAMIN E TPGS, E vitamini TPGS) based nanomedicines. It may be accelerated by optimization of preparation procedures for industry production and exploration of effective models to minimize the physiological difference between animal and human.

 

 

Kolliphor TPGS

 

 

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS): Çözünmezlik için çözüm

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) – D-alfa tokoferil polietilen glikol 1000 süksinat (TPGS) – zayf çözünür aktiflerin biyoyararlanmn dorudan artrabilen, E vitamininin suda çözünür bir türevidir. TPGS, genellikle farmasötik ve nutrasötik formülasyonlarda kullanlr.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin Temel Özellikleri

BASF’nin doal kaynakl E vitaminine dayanr

USP-NF monograf “Vitamin E Polietilen Glikol Süksinat” ile uyumludur

IPEC-PQG GMP kurallarna göre üretilmitir

Klorlu çözücü kullanlmaz

Ayrntl teknik ve yasal bilgiler mevcuttur

Hayat kurtaran ilaçlarn daha iyi datm

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), çözünürlüü düük ilaçlarn biyoyararlanmn ve datmn dorudan artrr.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) oral, topikal ve parenteral dozaj formlarnda kullanlabilir.

Ayrca diyet takviyeleri, kozmetik uygulamalar ve yiyeceklerde de kullanlmaktadr.

Müteriler için temel faydalar

Cognis, doal kaynakl E vitamini ve ilaç snf yardmc maddelerin önde gelen tedarikçisidir ve çözücüler konusunda önemli bir uzmanla sahiptir.

BASF, kendi E vitamini hammaddelerini kullanarak tutarl kaliteyi ve rekabetçi, güvenilir Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tedarikini garanti ediyor.

Sk endüstri gereksinimlerine uygun olarak BASF, eksiksiz destekleyici belgeler ile en yüksek üretim standartlarn korur.

BASF’nin TPGS’si yüksek çözünürlük etkinlii sunar.

BASF, küresel bir sat ann yan sra teknik ve yasal destek sunar.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) uygulamalar:

-laç çözücü

-Absorpsiyon arttrc

-Emülgatör

Lipit bazl ilaç teslimi için araç

-Doal E vitamini kayna

-Antioksidan

BASF, irketin Kankakee, Illinois (ABD) tesisinde üretilen Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin (Speziol TPGS Pharma, E vitamini polietilen glikol süksinat) farmasötik üretimini Minden, Almanya tesisine aktaracak. Geçiin 2014 ylnn ilk çeyreinde tamamlanmas bekleniyor.

“Minden tesisimizde Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) üretim kapasitesini geniletmek, BASF’n ilaç ve besin takviyesi pazarna olan ballnn bir baka örneidir. BASF Küresel Birimi laç Bileenleri ve Hizmetleri Küresel Birimi Yeni Ürünler Küresel Pazarlama Bakan Dr. Thorsten Schmeller, yer deitirme daha merkezi bir üretim tesisi yaratyor, üretim kurulumundaki karmakl azaltyor ve gelecekteki genileme için yer salyor “dedi. Minden sitesi, 70 yl akn süredir cGMP kapsamnda aktif farmasötik bileenler (API’ler) ve eksipiyanlar üretmektedir ve FDA ve Avrupa salk otoriteleri tarafndan düzenli olarak denetlenmektedir. Schmeller: “Minden tesisimizdeki ICH Q7 kalite yönetimi standartlar sayesinde, bir API’nin gereksinimlerini karlayan bir Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) snf sunabileceiz.”

Sorunsuz bir geçi taahhüdü

Minden’deki üretim tam olarak faaliyete geçene kadar BASF, geçi srasnda ilaç ve nutrasötik müterilerini tam olarak destekleyecek olan Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’yi Kankakee tesisinde üretmeye devam edecek. Schmeller, “Sorunsuz bir geçie izin vermesini beklediimiz cömert bir tedarik çakmas planladk,” diye ekledi. “Projeksiyonumuz, farmasötik uygulamalarda kullanlan ürünlerin geçii için gereken uygun kalifikasyon dönemini de hesaba katyor.” Minden tesisindeki Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) üretiminin 2013’ün ilk çeyreinde balamas bekleniyor.

Kankakee tesisi, BASF’nin beslenme ve salk ii için önemli bir üretim tesisi olmaya devam ediyor. irket, gda bileenlerinin yan sra, tesiste sabunlar, ampuanlar, deterjanlar, kaplamalar, mürekkepler ve yaptrclar için malzemeler üretmektedir.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), zayf çözünür aktif maddelerin biyoyararlanmn dorudan artrabilen, suda çözünür bir E vitamini türevidir. Yaygn olarak farmasötik ve beslenme formülasyonlarnda ve ayn zamanda kozmetikte kullanlr. Ek olarak, scak eriyik ekstrüzyonu (HME) gibi ilaç endüstrisinde ortaya çkan platform teknolojileri için çok faydal olan plastikletirici etkilere sahiptir.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), zayf çözünür aktif maddelerin biyoyararlanmn dorudan iyiletirebilen, suda çözünür bir E vitamini türevidir.

BASF Küresel Birimi laç Bileenleri ve Hizmetleri Küresel Pazarlama Yeni Ürünler bakan Thorsten Schmeller, yer deitirmenin merkezi bir üretim tesisi oluturduunu, üretim kurulumundaki karmakl azalttn ve gelecekteki genileme için yer saladn söyledi.

irket, Minden’deki üretim tamamen operasyonel hale gelene kadar Kankakee tesisinde Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) üretmeye devam edeceini söyledi.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), farmasötik ve beslenmede olduu kadar kozmetik formülasyonlarda da yaygn olarak kullanlmaktadr.

Minden tesisinde Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) üretimi büyük olaslkla 2013’ün ilk çeyreinde balayacak ve tamamlanmas Q1, 2014 olarak planlanyor.

 

 

D-ɑ-tokoferil polietilen glikol süksinat (Vitamin E Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) veya Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)), FDA tarafndan güvenli bir adjuvan olarak onaylanmtr ve ilaç datm sistemlerinde yaygn olarak kullanlmaktadr. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin biyolojik ve fizikokimyasal özellikleri, yüksek biyouyumluluk, ilaç çözünürlüünün artrlmas, ilaç geçirgenliinin iyiletirilmesi ve seçici antitümör aktivitesi gibi ilaç datmndaki uygulamalar için çok sayda avantaj salar. Özellikle Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), ATP’ye baml P-glikoproteinin aktivitesini inhibe edebilir ve tümördeki çoklu ilaç direncinin (MDR) üstesinden gelmek için güçlü bir eksipiyan olarak ilev görebilir. Bu derlemede, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) bazl ön ilaçlar, nitrik oksit donörü ve polimerler ve modifiye edilmemi Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) bazl formülasyonlar dahil olmak üzere Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin ilaç datmndaki son gelimelerini tartmay amaçlyoruz. Bu potansiyel uygulamalar, özellikle tümörlerin MDR’sinin üstesinden gelmek için ajanlarn terapötik etkisinin yan sra verme verimliliini artrmaya odaklanmtr. Ayrca, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tabanl nanotplarn klinik çevirisinin hala birçok zorlukla kar karya olduunu ve gelecekte Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) özellikleri ve temelli datm sistemi üzerinde daha ayrntl çalma gerektirdiini göstermektedir.

E vitamini, 1922’den beri üreme için temel bir faktör olarak tanmlanmtr 1. Daha fazla aratrma ile, antioksidan, anti-trombolitik ve dier terapötik etkileri içeren dier ilevlerle birlikte bulunmutur 2, 3. Bununla birlikte, E vitamininin zayf suda çözünürlüü vardr. 4. Vitamin E d-ɑ-tokoferil poli (etilen glikol) 1000 süksinat (basitçe Vitamin E Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) veya Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) olarak), E vitamini süksinatn poli (etilen glikol) (PEG) 1000 ile esterifikasyonu ile sentezlenmitir, doal E vitamini 5’in suda çözünür bir türevidir. Hidrofilik polar ba ksm ve lipofilik alkil kuyruu içeren amfifilik bir yapya sahiptir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), hidrofobik ilaçlarn mükemmel bir çözünürletiricisi, emülgatörü, geçirgenlii ve biyoyararlanm arttrcs olarak ilevselletirilebilir 6. Bu arada, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), birçok kanser türüne kar apoptojenik aktiviteyi indükledii gösterilen bir antikanser ajan olarak ilev görebilir. Kanser hücrelerinin mitokondrilerini hedefleyebilir, bu da apoptozun mitokondriyal araclarnn aktivasyonu için mitokondriyal dengesizlemeye neden olur 7. lginç bir ekilde, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin, normal hücrelere ve dokulara toksisite göstermezken tümör hücrelerinde seçici olarak apoptozu indükleyebilecei belgelenmitir 8.

Çoklu ilaç direnci (MDR), klinik kanser tedavisinde baarl kemoterapi için önemli bir engel olmaya devam etmektedir. Daha da kötüsü, onlarca yllk aratrmalar bu fenomenin hemen hemen her etkili ilaçta, hatta en yeni terapötik ajanlarda bile var olduunu tespit etmitir 9. Bu nedenle, ilaç direncinin etkili bir ekilde tersine çevrilmesi, kanser tedavisinde tatmin edici terapötik etkiye ulamada kritik bir rol oynamaktadr. Azaltlm ilaç ak, artan ilaç ak, deien ilaç metabolizmas ve tevik edilen anti-apoptotik mekanizma dahil olmak üzere MDR’de çeitli mekanizmalarn rol oynad gösterilmitir.10 Bunlar arasnda, ATP balayc kaset tayc P-glikoprotein (ABCB1) aracl ile ilaç ak MDR için en çok aratrlan ve karakterize edilen mekanizmalardan biridir. P-glikoprotein (P-gp), hidrofobik substrat ilaçlar balamak için 12 transmembran bölgeye ve ilaç moleküllerini 11 tamak için iki ATP balayc bölgeye sahiptir. P-gp substrat ilaçlarn hücre d bolua pompalayabilir ve böylece hücre içi ilaç birikimini azaltabilir. Son birkaç on ylda, MDR’nin üstesinden gelmek için P-gp inhibitörlerinin aratrlmasna önemli çabalar adanmtr. Pluronic, Tweens, Span ve Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) gibi çeitli noniyonik yüzey aktif cisimleri, 12, 13 P-gp aktivitesini inhibe etme kabiliyetine sahip bulunmutur. Bu yüzey aktif maddeler tarafndan P-gp inhibisyonunun tam mekanizmas belirsiz kalsa da, substrat balanmasnn 14 sterik bloke edilmesi, membran akkanlnn 15 deitirilmesi ve dar ak pompas ATPaz 16, 17’nin inhibisyonu potansiyel mekanizmalar olarak önerilmitir. laç datmnda yaygn olarak kullanlan bir adjuvan olarak Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), bu yüzey aktif maddeler arasnda en güçlü ve ticari olarak temin edilebilen P-gp inhibitörü olarak gösterilmitir. ATP’ye baml bir mekanizma yoluyla 19. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), mitokondriyi hedefleyebilir ve ilev bozukluuna neden olarak hücre içi ATP’nin tükenmesine neden olabilir. Azalm ATP seviyesi daha sonra P-gp’nin aktivitesini etkileyebilir ve hücre d bolua 20 ilaç akn azaltabilir. Ayrca, ATP’nin ATPase tarafndan hidrolizi, P-gp taycsn substrat ilaç ak için aktif bir konformasyonel duruma dönütürmek için kritiktir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin kendisi, P-gp’nin bir substrat olmad için ATPaz aktivitesini uyaramaz, ancak substratn indükledii ATPaz aktivitesini inhibe edebilir 21. Önceki çalmalarmzda, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin kemoterapötiklerin hücre içi birikimini ve sitotoksisitesini önemli ölçüde artrabildiini göstermitik. ilaca dirençli göüs adenokarsinom hücrelerine (MCF-7 / ADR) ve insan yumurtalk kanseri hücrelerine (A2780 / T) 22-24.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), FDA tarafndan güvenli bir farmasötik adjuvan olarak onaylandndan, biyoyararlanm arttrmak ve MDR’yi tersine çevirmek için yüzey aktif madde, çözücü, stabilizatör ve P-gp inhibitörü olarak ilaç verme sistemlerinde yaygn olarak kullanlmaktadr. Önceki incelemelerimizde 5, 6, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’yi moleküler bir biyomateryal olarak ve ilaç datmndaki orijinal uygulamasn tarttk. Bu derlemede, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin P-gp inhibe etme kabiliyeti ve dier temel özelliklerin avantajlarndan yararlanan son be ylda ilaç datmndaki ilerlemesine odaklandk. MDR’nin üstesinden gelmek ve terapötik ajanlar salamak için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) bazl ön ilaçlar, nitrik oksit (NO) donörü ve polimerlerin uygulamalarn özetledik. MDR’yi tersine çevirmek, oral kullanlabilirlii iyiletirmek ve ilaç nüfuzunu artrmak için uygulanan modifiye edilmemi Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) bazl formülasyonlar da tarttk. Bu incelemenin, MDR ve ilaç datmnn üstesinden gelmede Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) uygulamasna yeni bir ilham vereceini umuyoruz.

 

 

Sürfaktan olarak Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)

Zayf suda çözünürlük ve / veya zayf geçirgenlik, terapötik ilaçlarn maksimum aktivite göstermesinin önündeki balca engeller olarak kalr. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), ilaç uygulamasnda çözündürücü, absorpsiyon ve geçirgenlii artrc, emülgatör ve yüzey stabilizatörü olarak uygulanabilir. Özellikle biyofarmasötik snflandrma sistemi (BCS) snf Ⅱ ve Ⅳ ilaçlar 5, 6 için olmak üzere suda çözünürlüü düük veya geçirgen birçok ilaç için nano ilaçlarn veya dier formülasyonlarn imalatnda yaygn olarak kullanlmaktadr. Ayrca, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin güçlü bir ekilde sergiledii bildirilmitir. düük konsantrasyonda kilomikronlarn salglanmasndaki art ve barsak lenfatik tanmasn 25 arttrarak, ilaç absorpsiyon kabiliyetini daha da gelitirecektir.

Bir yüzey aktif madde olarak Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), farkl biyolojik engeller yoluyla ilaç emilimini artrma konusunda olaanüstü bir yetenek sergilemektedir. Örnein, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), serbest ilaçla karlatrldnda srasyla 25.7 kata ve 15.0 kata kadar doygunluk çözünürlüünü ve oral biyoyararlanm artrmak için repaglinid nanokristallerini imal etmek için kullanld. 26. Kamaralarn tanmas çalmalarnda, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) kolon dokusunda ilaç geçirgenliini artrabilir 27. Ek olarak, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin icariside Ⅱ’nn barsak absorpsiyon yetenei üzerindeki etkisi, Caco-2 tek tabakal model ve dört bölgeli sçan barsak perfüzyon modelinde aratrlmtr. Caco-2 tek katman modelinde, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin etkisiyle icariside value’nin görünür geçirgenlik katsaylar deeri artm ve da akm oran önemli ölçüde azalmtr. Dört bölgeli sçan barsak perfüzyon modeli aratrmas ayrca ileum ve kolon 28’de ikarisid ide’nin geçirgenliini önemli ölçüde artrdn göstermitir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) 29 varlnda rhodamine123 (Rh123) ile Caco-2 tek tabakal modelde benzer sonuçlar bulunmutur. lginçtir, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) yüksek ilaç kapsülleme verimlilii, küçük partikül boyutu ve hzl ilaç salm ile nanopartiküllerin imalatnda gözenek oluturucu bir ajan görevi görebilir. Ayrca, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), hidrofobik olarak ilaç formülasyonlarnn hazrlanmasnda emülgatör veya yüzey stabilizatörü olarak kullanlabilir. ksm hidrofobik ilac tutabilir ve hidrofilik ksm formülasyonlar stabilize edebilir.

MDR’nin üstesinden gelmek için bir P-gp inhibitörü olarak Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)

Kanser hücrelerinin ilaca direnci, kemoterapötik tedavide terapötik etkinlii snrlayabilir. ATP’ye baml membran tayc olarak P-gp, MDR’nin birincil nedenlerinden biri olmutur. Hücre içi ilaç birikimini azaltmak için P-gp substrat ilaçlarn dar pompalayabilir, böylece ilaca dirençli kanser tedavisinde kemoterapötik ilaçlarn sitotoksik etkisini azaltabilir. Geçtiimiz on yllar boyunca, MDR 31’in üstesinden gelmek için formülasyonlarda P-gp substrat ilaçlarn inhibitörle veya baz polimerleri P-gp inhibe etme kabiliyetine sahip bir miktar polimerle birletirmek için sürekli ilgi vardr. MDR tümör hücrelerinde ilacn hücre içi tutulmasn incelemek. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), serbest Rh123 ile karlatrldnda ilaca dirençli tümör hücrelerinde Rh123’ün hücre içi birikimini önemli ölçüde artrabilir; bu, ak sitometrisi ve konfokal mikroskop analizi 32 ile kantlanmtr. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin, üstesinden gelmek için P-gp aktivitesini etkili bir ekilde inhibe edebildii görülmektedir. MDR.

Dar ak taycs P-gp ATP’ye baml olduundan, ATP’nin tükenmesi MDR’nin üstesinden gelmede çok önemli bir rol oynar. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin MDR tersine çevirme etkisi esas olarak ikili etkilerine, ATP arzn ksaltmak için mitokondriyal solunum kompleksinin inhibisyonuna ve ATP kullanmn bloke etmek için substratn indükledii P-gp ATPaz aktivitesinin bastrlmasna atfedilir 20, 21, 33, 34.

Mitokondriyal solunum kompleksi Ⅱ, süksinat dehidrojenaz olarak da adlandrlr, trikarboksilik asit döngüsünün yan sra mitokondriyal solunum zincirinin önemli bir parças olan mitokondriyal elektron tanmasnda önemli bir rol oynar35. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), mitokondriyal solunum kompleksi ile balanabilir ve ardndan mitokondriyal disfonksiyon, hücre içi enerjinin önemli ölçüde tükenmesine neden olur 20, 36. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), mitokondride birikebilir ve kompleks Ⅱ aktivitesini inhibe edebilir ve sonuç olarak elektron transferini bozabilir ve kalsiyum kanaln aktive edebilir, bu da kalsiyumun ar yüklenmesi ve ardndan fonksiyon bozukluuna neden olur. mitokondri. Mitokondriyal disfonksiyon, mitokondriyal membran potansiyeli üzerindeki datc etki, azalm ATP seviyesi ve artan reaktif oksijen türleri (ROS) oluumu ile karakterizedir 37. Ayrca, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin mitokondriyal hedefleme yetenei mitokondriyal disfonksiyonu hzlandrabilir 32, 38. Substrat kaynakl P-gp ATPaz aktivitesi basklamas, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin ilaç da akn 21 azaltmas için bir baka mekanizmadr. ATPaz aktivitesi, substratn P-gp 39’un transmembran bölgelerine balanmasyla uyarlabilir. Daha sonra ATP, enerji beslemesi için adenozin difosfata (ADP) dönütürülür. ilaç ak. Klasik P-gp inhibitörü verapamilden farkl olarak, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), bir P-gp substrat deildir ve substrat balanmasnn rekabetçi inhibisyon etkisi göstermez. Balanma sahasnn sterik bloke etme fonksiyonu ve / veya P-gp’nin allosterik modülasyonu, ATPaz inhibisyon mekanizmas gibi görünmektedir.

Sinerjik antitümör etkiler için seçici bir antikanser ajan olarak Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), apoptozu indükleyebilir ve kanser hücrelerine kar seçici sitotoksik etkiler sergiler; bu, yan etkiyi azaltmak ve tedavi etkinliini artrmak için kemoterapötik ilaçlarla birletirilebilir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tedavisinden sonra normal ölümsüzletirilmi meme hücreleri ve kanser hücrelerinde önemli farkl yant vardr. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), meme kanseri hücreleri MCF-7 ve MDA-MB-231’de apoptotik sinyal yollarn tetikleyebilir ve G1 / S hücre döngüsü tutuklanmasna neden olabilir, ancak tümörijenik olmayan hücreler MCF-10A ve MCF-12F 40 üzerinde kayda deer bir etki yoktur. Tesadüfen, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), T hücreli akut lenfositik lösemi Jurkat klon E6-1 hücrelerinde apoptozu indükleyebilir, ancak insan periferik kan lenfositlerinde olumaz. Apoptoz, artan nükleer DNA fragmantasyonu, artm hücre döngüsü tutuklamas ve azalm mitokondriyal membran potansiyeli ile kantlanmtr 41. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin araclk ettii kanser hücrelerinin seçici apoptoz mekanizmalar karmaktr ve aadaki gibi sralanabilir:

 

 

ROS indükleyici

Α-tokoferil süksinata (α-TOS) benzer ekilde, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), mitokondriyal solunum kompleksinin ykm ve inhibisyonu yoluyla kanser hücresi apoptozunu indükleyebilir Ⅱ 33, 41. Sonraki elektron transfer zinciri bozulmas, ROS oluumunu destekleyebilir 20. Artm hücre içi ROS, bir apoptoz aracs, DNA hasarn ve lipid, protein ve enzimin oksidasyonunu indükleyerek hücre ykmna yol açabilir 42. Ayrca, tümör hücreleri daha fazla olabileceinden, ROS aracl apoptoz mekanizmasnn seçici antikanser aktivitesiyle ilikili olduu gösterilmitir. ROS’a normal hücrelere göre duyarl 43-45. TOS ile karlatrldnda, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), gelimi ROS oluturma kapasitesi 46 sergilemitir.

Anti-apoptotik proteinlerin aa regülasyonu

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), protein kinaz B’nin (PKB veya AKT) fosforilasyonunu inhibe edebilir ve ardndan kaspaz-baml programlanm hücre ölümü için kaspaz-3 ve -7’nin aktivasyonunu indükleyebilen anti-apoptotik proteinler Survivin ve Bcl-2’yi aa düzenleyebilir. Ayn zamanda, kaspazdan bamsz programlanm hücre ölümü ve G1 / S faz hücre döngüsü tutuklamas da meydana geldi 40, 41. Survivin ve Bcl-2 genellikle çou kanser hücresinde ar eksprese edilirken normal hücrelerde 47 önemli ölçüde azalr. Bu, hastaln ana nedeni olabilir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin seçici sitotoksisitesi.

DNA hasar

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) hem kaspaz baml hem de kaspaz bamsz DNA hasarna neden olabilir. Bu tür bir DNA hasar, androjen reseptörü pozitif (AR +) LNCaP hücrelerinde gözlendi, ancak hücresel mikro ortam ile ilgili olan AR-DU145 ve PC3 hücrelerinde görülmedi48.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX elenii

Doksorubisin (DOX) bir P-gp substrat ve geni spektrumlu bir antikanser ilaçtr. Bununla birlikte, DOX’un edinilen ilaç direnci, kanser tedavisinin ilerlemesindeki klinik uygulamalar için bir engeldir. Bao vd. 23, MDR’nin üstesinden gelmek için DOX’u Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ile birletirerek pH duyarl Schiff bazna bal bir ön ilaç, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CH = N-DOX (TD olarak da adlandrlr) gelitirdi. Bu ön ilaç, fizyolojik durumda kararl miseller halinde kendi kendine birleebilir ve bir PEGile lipit ekleyerek in vivo tümör hedeflemesi ve uzun kan dolam gerçekletirebilir. Sistem, integrin reseptör ligand peptid siklik RGD’den (cRGD) tümör hedeflemeyi, PEGile lipidden uzun sirkülasyon özelliini, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) materyalinden MDR’yi aan ve Schiff bazl balaycdan uyarana duyarl salm. Formüle edilen hibrit miseller, pH’a duyarl ilaç salm profili ve endo / lizozomal asidik ortam simüle eden pH 5.0 tamponunda bariz partikül boyutu deiiklii gösterdi. Ayrca, ak sitometrisi ve konfokal mikroskop analizi ile DOX almnn arttn ve serbest ilaca kyasla in vivo farmakokinetik yoluyla artm tutmay gösterdi. DOX, inkübasyon srasnda ilaca duyarl MCF-7 hücrelerinde iyi tutma sergilemitir. Aksine, serbest ilaç, çok düük DOX içerii gösterdi ve uzun inkübasyon süresinde bile MCF-7 / ADR hücrelerinde önemli ölçüde azaltlm tutulma gösterdi. Hem verapamil hem de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin P-gp inhibitörleri, MCF-7 / ADR hücrelerinde ilaç birikimini artrabilir. Ön ilaç miselleri, MCF-7 / ADR hücrelerinde Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve DOX karm ile benzer ilaç alm ve tutma eilimini elde etti. çselletirilmi misellerden hzla ayran Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin P-gp aktivitesini inhibe edebilecei ve MDR tümörlerine kar müteakip sitotoksisite için DOX’u koruyabilecei görülmektedir. Hibrid misellerin yar maksimal inhibitör konsantrasyonlar (IC50), 72 saatlik inkübasyondan sonra serbest ilacnkinden 95 kat daha düük olduu için, MCF-7 / ADR hücrelerindeki hibrit miseller tarafndan gelitirilmi sitotoksisite ve apoptoz indüklendi. Antitümör etkililik mekanizmas, hücre içi ROS üretimi, mitokondriyal membran potansiyelinin (m) deiimi ve hücre içi ATP seviyesinin (ekil ekil 22B) analizi yoluyla daha da aratrlmtr. ROS birikimi, azalm mitokondriyal membran potansiyeli ve hibrit misellerden azalm ATP üretimi, mitokondrinin ‘hücresel enerji santrallerinden’ enerji beslemesini keserek Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tarafndan P-gp inhibisyonuna katkda bulunabilir. Ön ilaç, MCF-7 / ADR tümörü üzerinde önemli büyüme inhibisyonu (ekil 22C) ve ayrca, hibrid miseller üzerinde dekore edilmi cRGD ile murin melanoma B16F10 ve hepatokarsinoma H22’de tümör büyümesi / metastaz inhibisyonu sergiledi. Etkili kanser tedavisi için rasyonel ön ilacn tasarm yoluyla uygulama sistemindeki yükü hafifletmek ve nanotp terapötik verimliliini artrmak için güvenli ve basit bir ön ilaç platformu salad.

Dier baz Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX ön ilaçlar da 55-57 olarak tasarlanm ve ina edilmitir. Feng’in 55 grubu, süksinik anhidrit modifiye edilmi Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’yi DOX ile dorudan birletirerek Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX ön ilacn gelitirdi. Ön ilaç, gelimi hücre alm ve sitotoksisite gösterdi. Serbest ilaçla karlatrldnda, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX ön ilacnda srasyla 4,5 ve 24 kat yarlanma ömrü (t1 / 2) ve eri altndaki alan (AUC) bulunmutur. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX-folik asit konjugat (Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX-FOL) daha yüksek terapötik etkilere ve daha az yan etkiye sahip hedefli kemoterapi için tantld 56. Ayrca, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX ön ilac, kombinasyonel paket ilaçlara da uygulanabilir. terapi. Hou vd. 57, bir aside duyarl Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX ön ilacn ilk olarak pH’a duyarl cis-akonitik anhidrit ile modifiye edilmi DOX sentezleyerek ve ardndan Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ile konjuge ederek oluturdu. Ön ilaç, nanopartiküller halinde kendi kendine birleebilir. Bu Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX ön ilaç nanopartiküllerine a duyarl hale getirici klorin e6 (Ce6), yakn kzlötesi floresan görüntüleme ve tümöre kar kemoterapi ve fotodinamik tedavinin kombinasyonu için yüklendi. Nanopartiküller, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve DOX arasndaki aside duyarl balaycnn neden olduu pH’a duyarl DOX ve Ce6 salm özellikleri sergiledi. Ayrca, küçük hücreli olmayan akcier kanserinde hücre alm, kanser hücresi apoptozu ve önemli büyüme basklanmas üzerinde sinerjik etkiler gösterdi (A549).

 

 

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-PTX konjugat

Paklitaksel (PTX), zayf çözünürlük ve geçirgenlie sahip bir BCS snf Ⅳ ilaç ve ayn zamanda etkili ilaç iletimini ve MDR tümör tedavisini engelleyen bir P-gp substratdr. Zhang’n 58. grubu, tümöre kar sitotoksisite için PTX’i ve P-gp inhibisyonu için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) aktif bileenini serbest brakmak için hücre içi redoks ortamnda (yüksek GSH konsantrasyonu) hzla ayrtrlabilen redoksa duyarl bir ön ilaç Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX sentezledi. Ön ilaç, kararl miseller halinde kendi kendine birleebilir ve pasif tümör hedeflemesini gelimi nüfuz etme ve tutma (EPR) etkisi yoluyla gerçekletirebilir. Tepkisiz ester ba ile konjuge PTX ön ilac Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX ile karlatrldnda, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX daha iyi stabilite ve hücre içi indirgeyici ortam tarafndan tetiklenen in vitro sürekli ilaç salm sergilemitir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX misellerinin artan stabilitesi, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX’in tek iki karbon balaycsna kyasla Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve PTX arasndaki yumuak sülfür balaycsna atfedilebilir. Taxol® ve Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX’in klinik formülasyonu ile karlatrldnda, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX miselleri, redokstan hzl ayrm Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin neden olabilecei ilaca dirençli A2780 / T hücreleri için artm hücre içi PTX birikimi sergilemitir. -hassas ön ilaç. Rh123, MDR tümöründe ilaç tutulmasn deerlendirmek için P-gp substratnn bir model ilac olarak kullanld. Hücreler verapamil veya ön ilaçlar ile tedavi edildiinde, Rh123 floresans younluu serbest Rh123 ile karlatrldnda artmtr. Özellikle, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX ile karlatrldnda Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX’te çok daha yüksek floresans younluu sergilendi, bu da ayrm Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’den P-gp inhibisyon özelliini dorulad. Beklendii gibi, bu fonksiyonel ön ilaç misel, A2780 / T hücrelerinde PTX’in sitotoksisitesini arttrd. Ayrlamayan Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX ön ilac ve Taxol® ile karlatrldnda, uyarya duyarl ön ilaç IC50’yi düürdü ve MDR tümörünün apoptozunu / nekrozunu arttrd. n vivo deerlendirme ayrca bu ön ilaç miselinin kanser tedavisi üzerindeki potansiyelini, artan AUC, uzatlm tl / 2, tümörde gelimi ilaç dalm ve azaltlm yan etkilerle önemli tümör büyümesi inhibisyonu olarak gösterdi.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatin konjugat

Sisplatin testis, yumurtalk, servikal, ba ve boyun ve küçük hücreli olmayan akcier kanserlerinde yaygn olarak kullanlmaktadr. Bununla birlikte, klinik uygulama, düük çözünürlük, nefrotoksisite, iddetli periferik nörotoksisite, doal ve edinilmi ilaç direnci için snrldr 59. Feng’in 60 grubu, su çözünürlüünü iyiletirmek ve sisplatinin nörotoksisitesini azaltmak için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatin ön ilacn gelitirmitir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatin, yüksek ilaç yükleme kapasitesi ile kendi kendine misellere monte edilebilir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatin ön ilacnda, serbest ilaca kyasla HepG2 hepatokarsinoma hücrelerine kar daha yüksek hücre alm ve sitotoksisite bulundu. Ön ilaç miselleri ayrca, serbest cisplatine kyasla SH-SY5Y nöroblast benzeri hücreler için daha yüksek IC50 deeriyle önemli nöroprotektif etkiler gösterdi. Ek olarak, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), insan epidermal büyüme faktörü reseptör 2 (HER2) ekspresyonu 61’in yüksek düzeyde olduu meme kanseri ile urarken güçlü bir antikanser ajandr. Mitokondriyal solunum kompleksi Ⅱ ve bunu takip eden ROS oluumunun inhibisyon etkisi ile ilgili olabilir, HER2 reseptörü tirozin kinaz sinyal yolu 33 yoluyla hücre apoptozuna neden olur. Mi ve arkadalar 62, HER2’de iyi tümör inhibisyonu için cisplatin, dosetaksel (DTX) ve Herceptin’in birlikte iletimi için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatin ön ilaç nanopartiküllerinin hedeflenmi bir datm sistemini gelitirdi. ar eksprese edilen göüs kanserleri. Poli (laktik asit) (PLA) -Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-COOH ve Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatin, meme kanserinin multimodalite tedavisi için nanopartiküller üretmek için kartrld. Çoklu ilaç yüklü nanopartiküller, serbest ilaçlarn karmna kyasla yüksek HER2 ekspresyonu ile SK-BR-3 hücreleri için çok daha düük IC50 deeri sergiledi.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU elenii

Liu’nun 63, 64 grubu, MDR’nin üstesinden gelmek için hidrofobik ilaç PTX ve hidrofilik ilaç 5-florourasilin (5-FU) birlikte verilmesi için çok ilevli nanopartiküller gelitirdi. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU, basitçe süksinoyatlanm Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin 5-FU ile konjuge edilmesiyle sentezlendi. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU ön ilac ve PTX’ten oluan nanopartiküller, bireysel ajan tedavisine kyasla MDR tümörüne kar artm sitotoksisite gösterdi 64. Ayrca PTX-Vitamin E ve Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU ön ilac ile nanoemülsiyonlar gelitirdiler. laçlarn birlikte verilmesi ile nanoemülsiyonlar, insan epidermal karsinom hücre hatt KB-8-5 63’te PTX direncinin üstesinden gelmenin sinerjik etkisini sergilemitir. Etkili antikanser aktivitesi, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin P-gp inhibisyon etkisinden ve PTX’in sinerjistik etkisinden kaynaklanmtr. Kanser öldürme için çeitli sinyal yollarn ayn anda hedefleyebilen 5-FU.

Hedeflenen ligand konjuge Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)

RGD, avp3 integrin reseptörleri ar ekspresyonu olan tümörler için kanser tedavisinde potansiyel bir hedefleme ligand olarak uygulanmtr. Li’nin grubu 112, ilaç direncinin üstesinden gelmek için Pluronic P85-polietilenimin, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve iRGD-Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’yi kartrarak PTX ve Survivin shRNA birlikte yüklenmi hedeflenen nanopartikülleri formüle etti (ekil 55A). Nanopartiküller, hem A549 hem de A549 / T hücrelerinde artm hücre alm, RNA enterferans etkisi ve sitotoksisite sergiledi. Ayrca, hedeflenen nanopartiküllerin, Taxol® ile karlatrldnda, birlikte datm sisteminden önemli antitümör etkileri gösterdii kantlanmtr. RGD-konjuge Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), insan glioblastoma tümöründe (U87MG) 113 iyi büyüme inhibisyonu sergileyen E vitamini süksinat (VES) ile alanm kitosan oligosakarit ile kartrlarak hedeflenen miselleri hazrlamak için de kullanlmtr. TLyp-1 peptidi, nöropilin-1 reseptörü (NRP-1). Nanopartiküllerin yüzeyini tümör ve anjiyogenez hücreleri üzerinde ar eksprese edilmi NRP-1 olarak dekore etmek için hedefleyici bir peptit olarak da kullanlabilir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), önce tLyP-1 peptidi ile birletirildi ve daha sonra bir nanopresipitasyon yöntemiyle DOX yüklü nanopartikülleri imal etmek için PLA-Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve Ce6-konjuge Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ile kartrld. Elde edilen nanopartiküller, vasküler ekstravazasyonu artrabilir ve kombinasyonel kemo-fotodinamik tedavinin sinerjik antitümör etkileri için tümördeki ilaçlarn penetrasyonunu ve birikimini iyiletirebilir (ekil 55B) 114. Ek olarak, transferrin konjuge Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin bir tür terapötik miselleri uyguland. ezamanl kanser görüntüleme ve tedavisi için DTX ve altn kümelerin hedeflenen birlikte datm için. Miseller, srasyla Taxotere® ve hedeflenmemi misellere kyasla transferrin reseptörlerinin ar ekspresyonuna sahip MDA-MB-231-luc göüs kanseri hücrelerinde 71.7 kat ve 4.7 kat daha düük IC50 deerleri ile gelimi sitotoksisite sergiledi. In vivo görüntüleme ve antitümör etkinlii ayrca tümör tayan farelerde 115 kantlanmtr.

Deitirilmemi Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) bazl formülasyonlar

Yukarda bahsedilen temel özelliklere göre, modifiye edilmemi Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), ilaç verme sisteminde çok ilevli bir malzeme olarak kullanlabilir. Bu ilevler, MDR’nin almas, oral ilaç biyoyararlanmnn iyiletirilmesi ve ilaç nüfuzunun tevik edilmesi olarak özetlenebilir.

MDR’nin üstesinden gelmek için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) bazl formülasyonlar

Bilimsel aratrmalar, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin, kanser tedavisinde MDR’nin tersine çevrilmesi için nano ilaçlarn imalatnda ilaç taycs ve P-gp inhibitörü olarak kullanlabileceini dorulamtr (Tablo Tablo 33). Gao vd. 120, pazarlanan enjeksiyona kyasla akut toksisitenin 2 kat ortalama öldürücü dozu (LD50) ve gelimi farmakokinetik sergileyen Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) stabilize PTX nanosüspansiyonlarn gelitirdi. Nanosüspansiyonlar ayrca, i.v. Uygulama 121. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), MCF-7 / ADR hücrelerinde ilaç direncinin üstesinden gelmek için PTX nanoemülsiyonlarn hazrlamak için de kullanld. Nanoemülsiyonlar, önemli P-gp inhibisyonu ve% 94 tümör inhibisyon oran sergiledi (ekil ekil 66A) 18.

laç nüfuzunu tevik etmek için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) bazl formülasyonlar

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), deri veya kornea gibi fizyolojik engeller boyunca ilaç geçiini iyiletirebilir. Transdermal ilaç verilmesi ve göz hastalklarnn tedavisi için birçok formülasyon oluturmak için uygulanabilir.

 

 

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve hidroksipropil metilselüloz (HPMC) ile ibuprofen süper doymu çözelti, transdermal ilaç verme sistemlerinde uygulanabilen dier çözündürücü / polimer sistemlerine kyasla daha yüksek geçirgenlik oran ve daha uzun kristalleme balangc gösterdi 155. Bu çalmadan sonra, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) / HPMC nanosüspansiyonlar, Skin-A Örnek Olay 156 yoluyla çözücü olarak Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ile ibuprofenin geçirgenliini iyiletirdi. Ayrca, kutanöz mantar enfeksiyonlarn tedavi etmek için amfoterisin B’nin topikal iletimi için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) nanoemülsiyon bazl nanojeller oluturuldu. Nanojeller, pazarlanan topikal formülasyona kyasla domuz kulak derisinde 3,9 kat daha yüksek cilt birikimi ve Aspergillus niger ve Candida albicans’a kar 2,0 kat daha yüksek antifungal aktivite sergiledi. Nanojeller derinin daha derin katmanlarna nüfuz edebilir. Karbopol (980 NF) baznda penetrasyon arttrc olarak Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) kombinasyonu ile bir antifungal ajan olan griseofulvin topikal bir formülasyonu hazrland. Formülasyon, ciltte gelimi ilaç geçirgenlii ve tutulmas sergiledi ve yüzeysel mantar enfeksiyonunun tedavisi için uygun alternatif olarak büyük potansiyel gösterdi 158.

Transdermal ilaç datmna paralel olarak, korneada ilaç translokasyonunu desteklemek için Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) uyguland. laçlarn suda zayf çözünürlüü, penetrasyonu snrlayacak ve göz hastalklar için farmakolojik etkileri kstlayacaktr. Cholkar vd. 159 Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve oktoksinol-40 (Oc-40) ile deksametazon yüklü miseller hazrland (arlk oran 4.5: 2.0). Kark polimerler, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) (arlkça% 0.025) ve Oc-40 (arlkça% 0.107) ile karlatrldnda daha düük CMC (arlkça% 0.012) sergiledi. Formülasyonlarn güvenlii, tavann birincil korneal epitel hücreleri üzerindeki sitotoksisiteden kantlanmtr. Rapamisin yüklü miseller ayrca, insan retina pigment epitel ve tavan birincil korneal epitel hücreleri üzerinde düük in vitro sitotoksisite olarak iyi tolerans sergileyen Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ve Oc-40 ile hazrland. Miseller ayrca, vitröz mizah içine ihmal edilebilir ilaç bölünmesi, ancak hedeflenen retina-koroid 160 bölgesinde çok yüksek ilaç seviyesi olarak klinik uygulamada fizibilite sergiledi. Dahas, in situ CUR jelleri, iyon duyarl Pluronic P123 / Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) kark datlarak hazrland. gellan sakz çözeltisinde miseller. Jeller, CUR solüsyonu 161 ile karlatrldnda daha iyi korneal penetrasyon ve daha uzun oküler retansiyon sergiledi.

uraya gidin:

Sonuçlar ve perspektifler

Bu derlemede, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin ilaç datmndaki özelliklerini ve son dönemdeki ilerlemesini özetledik. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin ilaç teslimi için yararlar aada listelenmitir. (i) Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), FDA tarafndan yüksek biyouyumlulua sahip güvenli bir farmasötik adjuvan olarak onaylanmtr. (ii) Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), MDR’nin üstesinden gelmek için etkili bir P-gp inhibitörü olarak hizmet edebilir. (iii) Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin kendisi, tümör hücrelerine kar seçici toksisiteye sahip bir antikanser ajan olarak hareket edebilir. (iv) Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), terapötik ajanlarn artan çözünürlüü ve stabilitesi, gelimi PK / PD, artrlm tedavi etkinlii ve azaltlm yan etkiler ile kanser tedavisinde umut verici bir strateji olarak gösterilen nanotp gelitirmek için nanoteknoloji ile kolayca birletirilebilir. Burada Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tabanl ön ilaçlar, NO donörleri ve polimerler dahil olmak üzere Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tabanl nanotplar ve Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin ilaç datmndaki özelliklerinden, özellikle MDR’nin üstesinden gelmede güçlü etkiden yararlanan deitirilmemi Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tabanl formülasyonlar dahil olmak üzere birçok örnei tarttk. Bu örnekler, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin MDR’nin üstesinden gelmek, oral biyoyararlanm iyiletirmek, ilaç nüfuzunu tevik etmek ve dier ilevler için potansiyel ve ümit verici uygulamalarn açkça gösterdi.

P-gp inhibisyonu, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin MDR’nin üstesinden gelmek için ana mekanizmas olarak geni çapta kabul edilmitir. Mitokondriye baml P-gp pompa inhibisyonu iyi karakterize edilmi olmasna ramen, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tarafndan ATPaz inhibisyonunun tam mekanizmas hakknda çok az ipucu vardr. ATPaz inhibisyonunun, substrat balanmasnn sterik bloke edilmesi, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin P-gp nükleotid balanma alanlar ile dorudan etkileimi veya bir allosterik modülasyon 34 yoluyla P-gp fonksiyonunu dolayl olarak etkilemesi yoluyla elde edilip edilmedii belirsizliini korumaktadr. Ayrca, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ile çalmayabilir. tümör progresyonu srasnda tümör heterojenitesinden elde edilen ilaç direnci. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin tümör invazyonunu ve metastaz önleyebilecei bildirilmitir. Altta yatan mekanizmalar bilinmemektedir ve tümör metastaznda Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin daha kapsaml uygulamas için hala aratrlmas gerekmektedir. Ayrca, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin kanser immünoterapisi için a gelitirmede bir adjuvan olarak kullanlabilmesi nedeniyle Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin baklk sistemi üzerindeki etkisinin aratrlmas gerekmektedir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tabanl formülasyonlara gelince, tümör mikro ortamndaki nanoformülasyonlarn kesin uyarana duyarl özelliini ve derinlemesine nüfuz etmesini gerçekletirme konusundaki snrlamalar, bu nanotplarn yaygn olarak uygulanmasnn önünde hala engeller olarak kalmaktadr. Hedeflenen uygulama verimliliini artrmak, kontrollü ilaç salnmn salamak ve terapötiklerin tümör içine penetrasyonunu artrmak için daha etkili stratejilerden yararlanlmaldr. Klinik çeviri, çok ilevli özelliklere sahip basit yapya odaklanlmas gereken nanotp gelitirmenin nihai hedefidir. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)’nin biyouyumluluundan ve çoklu ilevlerinden yararlanan Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tabanl nanotplar, farmasötiklerde “moleküler ekonomi” özellii açsndan umut verici olabilir. Bununla birlikte, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) nanotplarn hazrlanmas hala laboratuvar ölçeindedir ve yeni nanotp gelitirmedeki ilerleme nispeten yavatr, bu da Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) tabanl nanotplarn baarl klinik çevirisini engellemektedir. Endüstri üretimi için hazrlk prosedürlerinin optimizasyonu ve hayvan ve insan arasndaki fizyolojik fark en aza indirmek için etkili modellerin aratrlmasyla hzlandrlabilir.

 

 

Kolliphor TPGS

 

 

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS): Solution d’insolubilité

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) – succinate de D-alpha tocophéryl polyéthylène glycol 1000 (TPGS) – est un dérivé hydrosoluble de la vitamine E qui peut directement améliorer la biodisponibilité des actifs peu solubles. Le TPGS est couramment utilisé dans les formulations pharmaceutiques et nutraceutiques.

Principales caractéristiques de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)

À base de vitamine E de source naturelle de BASF

Conforme à la monographie USP-NF «Succinate de polyéthylène glycol de vitamine E»

Produit selon les directives IPEC-PQG GMP

Aucun solvant chloré utilisé

Informations techniques et réglementaires détaillées disponibles

Amélioration de la délivrance de médicaments vitaux

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) augmente directement la biodisponibilité et la délivrance de médicaments peu solubles.

Le TPGS peut être utilisé sous des formes posologiques orales, topiques et parentérales.

Il est également utilisé dans les compléments alimentaires, les applications cosmétiques et alimentaires.

Avantages clés pour les clients

Cognis est l’un des principaux fournisseurs de vitamine E de source naturelle et d’excipients de qualité pharmaceutique, et possède une expertise considérable dans les solubilisants.

En utilisant ses propres matières premières en vitamine E, BASF garantit une qualité constante et un approvisionnement compétitif et fiable en Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS).

Conformément aux exigences strictes de l’industrie, BASF maintient les normes de fabrication les plus élevées, avec une documentation complète à l’appui.

Les TPGS de BASF offrent une grande efficacité de solubilisation.

BASF propose un réseau de vente mondial ainsi qu’une assistance technique et réglementaire.

Applications de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS):

-Solubilisant de médicaments

-Augmenteur d’absorption

-Émulsifiant

-Véhicule pour l’administration de médicaments à base de lipides

-Source de vitamine E naturelle

-Antioxydant

BASF transférera la production pharmaceutique de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) (Speziol TPGS Pharma, succinate de polyéthylène glycol de vitamine E), fabriqué sur le site de Kankakee, Illinois (États-Unis), à son usine de Minden, en Allemagne. La transition devrait être achevée au premier trimestre de 2014.

«L’extension de la capacité de fabrication de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) sur notre site de Minden est un autre exemple de l’engagement de BASF sur le marché des produits pharmaceutiques et des compléments alimentaires. La délocalisation crée une installation de production plus centralisée, réduit la complexité de la configuration de la production et offre de la place pour une expansion future », a déclaré le Dr Thorsten Schmeller, responsable du marketing mondial des nouveaux produits à la division mondiale des ingrédients et services pharmaceutiques de BASF. Le site de Minden fabrique des principes actifs pharmaceutiques (API) et des excipients sous cGMP depuis plus de 70 ans et est régulièrement inspecté par la FDA et les autorités sanitaires européennes. Schmeller: «Grâce aux normes de gestion de la qualité ICH Q7 sur notre site de Minden, nous serons en mesure de proposer une qualité Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) qui répond aux exigences d’une API.»

Engagement pour une transition transparente

Jusqu’à ce que la production à Minden soit pleinement opérationnelle, BASF continuera à fabriquer du Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) sur le site de Kankakee, qui soutiendra pleinement les clients pharmaceutiques et nutraceutiques pendant la transition. «Nous avons prévu un généreux chevauchement des approvisionnements qui, selon nous, permet une transition sans heurts», a ajouté Schmeller. «Notre projection prend également en compte la période de qualification appropriée requise pour la transition des produits utilisés dans les applications pharmaceutiques.» La production de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) sur le site de Minden devrait démarrer au premier trimestre 2013.

Le site de Kankakee reste une installation de production importante pour l’activité nutrition et santé de BASF. Outre les ingrédients alimentaires, l’entreprise fabrique des ingrédients pour savons, shampooings, détergents, revêtements, encres et adhésifs sur le site.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) est un dérivé hydrosoluble de la vitamine E qui peut directement améliorer la biodisponibilité des substances actives peu solubles. Il est couramment utilisé dans les formulations pharmaceutiques et nutritionnelles, mais aussi en cosmétique. De plus, il a des effets plastifiants très bénéfiques pour les technologies de plate-forme émergentes de l’industrie pharmaceutique telles que l’extrusion thermofusible (HME).

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) est un dérivé hydrosoluble de la vitamine E qui peut directement améliorer la biodisponibilité des substances actives peu solubles.

BASF Global Business Unit Pharma Ingredients & Services Global Marketing New Products Head, Thorsten Schmeller, a déclaré que la délocalisation créait une installation de production centralisée, réduisant la complexité de la configuration de la production, tout en laissant la place à une expansion future.

La société a déclaré que jusqu’à ce que la production à Minden soit pleinement opérationnelle, elle continuerait à fabriquer du Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) sur le site de Kankakee.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) est couramment utilisé dans les produits pharmaceutiques et nutritionnels, ainsi que dans les formulations cosmétiques.

La production de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) sur le site de Minden devrait débuter au premier trimestre 2013 et s’achever au premier trimestre 2014.

 

 

Le succinate de D-ɑ-tocophéryl-polyéthylène glycol (Vitamine E Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ou Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)) a été approuvé par la FDA comme adjuvant sûr et largement utilisé dans les systèmes d’administration de médicaments. Les propriétés biologiques et physicochimiques de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) offrent de multiples avantages pour ses applications dans l’administration de médicaments tels qu’une biocompatibilité élevée, une amélioration de la solubilité des médicaments, une amélioration de la perméation des médicaments et une activité antitumorale sélective. Notamment, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut inhiber l’activité de la glycoprotéine P dépendante de l’ATP et agir comme un excipient puissant pour surmonter la résistance multi-médicamenteuse (MDR) dans la tumeur. Dans cette revue, nous visons à discuter des avancées récentes de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) dans l’administration de médicaments, y compris les promédicaments à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), le donneur d’oxyde nitrique et les polymères, et les formulations à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) non modifiées. Ces applications potentielles sont axées sur l’amélioration de l’efficacité de la délivrance ainsi que sur l’effet thérapeutique des agents, en particulier pour surmonter la MDR des tumeurs. Cela démontre également que la traduction clinique des nanomédicaments à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) est toujours confrontée à de nombreux défis, ce qui nécessite une étude plus détaillée des propriétés du Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et du système de délivrance basé à l’avenir.

La vitamine E a été identifiée comme un facteur essentiel pour la reproduction depuis 1922 1. Après des recherches plus poussées, elle a été trouvée avec d’autres fonctions impliquant des effets antioxydants, anti-thrombolytiques et autres effets thérapeutiques 2, 3. Cependant, la faible solubilité dans l’eau de la vitamine E a limité considérablement son application 4. Vitamine E d-ɑ-tocophéryl poly (éthylène glycol) 1000 succinate (simplement sous forme de vitamine E Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ou Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)), synthétisée par estérification du succinate de vitamine E avec du poly (éthylène glycol) (PEG) 1000, est un dérivé hydrosoluble de la vitamine E naturelle 5. Il a une structure amphiphile comprenant une partie de tête polaire hydrophile et une queue alkyle lipophile. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut être fonctionnalisé comme un excellent solubilisant, émulsifiant, améliorant la perméation et la biodisponibilité des médicaments hydrophobes 6. Pendant ce temps, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut agir comme un agent anticancéreux, qui a été démontré pour induire une activité apoptogène contre de nombreux types de cancer. Il peut cibler les mitochondries des cellules cancéreuses, entraînant la déstabilisation mitochondriale pour l’activation des médiateurs mitochondriaux de l’apoptose 7. Fait intéressant, il a été documenté que Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut induire sélectivement l’apoptose dans les cellules tumorales tout en présentant une non-toxicité pour les cellules normales et les tissus 8.

La résistance multidrogue (MDR) reste un obstacle important à la réussite de la chimiothérapie dans le traitement clinique du cancer. Pire encore, des décennies de recherche ont identifié que ce phénomène existe dans presque tous les médicaments efficaces, même les agents thérapeutiques les plus récents. Il a été démontré que divers mécanismes sont impliqués dans la MDR, notamment la diminution de l’afflux de médicaments, l’augmentation de l’efflux de médicaments, la modification du métabolisme des médicaments et la promotion du mécanisme anti-apoptotique 10. Parmi eux, l’efflux de médicaments médié par la glycoprotéine P du transporteur de cassette de liaison à l’ATP (ABCB1) est l’un des mécanismes de MDR les plus étudiés et les plus caractérisés. La P-glycoprotéine (P-gp) a 12 régions transmembranaires pour lier les médicaments de substrat hydrophobe et deux sites de liaison à l’ATP pour transporter les molécules de médicament 11. Elle peut pomper les médicaments de substrat de la P-gp vers l’espace extracellulaire et ainsi diminuer l’accumulation intracellulaire de médicament. Au cours des dernières décennies, des efforts considérables ont été consacrés à l’exploration des inhibiteurs de la P-gp pour surmonter la MDR. Plusieurs tensioactifs non ioniques tels que Pluronic, Tweens, Span et Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) ont été trouvés avec la capacité d’inhiber l’activité de la P-gp 12, 13. Bien que le mécanisme exact de l’inhibition de la P-gp par ces tensioactifs reste incertain, le blocage stérique de la liaison au substrat 14 , l’altération de la fluidité de la membrane 15 et l’inhibition de la pompe d’efflux ATPase 16, 17 ont été proposées comme mécanismes potentiels. En tant qu’adjuvant largement utilisé dans l’administration de médicaments, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) s’est avéré être l’inhibiteur de la P-gp le plus puissant et disponible dans le commerce parmi ces tensioactifs 18. En tant que transporteur membranaire de la famille de cassettes de liaison à l’ATP, la P-gp peut pomper le médicament substrat via un mécanisme dépendant de l’ATP 19. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut cibler les mitochondries et provoquer son dysfonctionnement, entraînant une déplétion de l’ATP intracellulaire. Le niveau d’ATP réduit peut alors influencer l’activité de la P-gp et diminuer l’efflux du médicament vers l’espace extracellulaire 20. En outre, l’hydrolyse de l’ATP par l’ATPase est essentielle pour convertir le transporteur de la P-gp en un état conformationnel actif pour l’efflux du médicament substrat 16 . Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) lui-même ne peut pas stimuler l’activité ATPase car il n’est pas un substrat de la P-gp, mais peut inhiber l’activité ATPase induite par le substrat 21. Dans nos travaux précédents, nous avons démontré que Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut augmenter de manière significative l’accumulation intracellulaire et la cytotoxicité des agents chimiothérapeutiques. aux cellules d’adénocarcinome du sein résistantes aux médicaments (MCF-7 / ADR) et aux cellules cancéreuses de l’ovaire humain (A2780 / T) 22-24.

Depuis que Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) a été approuvé par la FDA en tant qu’adjuvant pharmaceutique sûr, il a été largement utilisé dans les systèmes de délivrance de médicaments en tant que surfactant, solubilisant, stabilisant et inhibiteur de la P-gp pour améliorer la biodisponibilité et inverser la MDR. Dans nos revues précédentes 5, 6, nous avons discuté de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) en tant que biomatériau moléculaire et de son application originale dans l’administration de médicaments. Dans cette revue, nous nous sommes concentrés sur les progrès de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) dans l’administration de médicaments au cours des cinq dernières années, qui ont tiré parti de la capacité d’inhibition de la P-gp et d’autres propriétés de base. Nous avons résumé les applications des promédicaments à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), du donneur d’oxyde nitrique (NO) et des polymères pour surmonter la MDR et administrer des agents thérapeutiques. Nous avons également discuté des formulations à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) non modifiées appliquées pour inverser la MDR, améliorer la disponibilité orale et augmenter la perméation des médicaments. Nous espérons que cet examen donnera une nouvelle inspiration pour l’application de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) pour surmonter la MDR et l’administration de médicaments.

 

 

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) comme tensioactif

Une mauvaise hydrosolubilité et / ou une mauvaise perméabilité restent les principaux obstacles pour que les médicaments thérapeutiques exercent une activité maximale. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut être appliqué comme solubilisant, amplificateur d’absorption et de perméation, émulsifiant ainsi que stabilisateur de surface dans l’administration de médicaments. Il a été largement utilisé dans la fabrication de nanomédicaments ou d’autres formulations pour de nombreux médicaments peu solubles ou perméables dans l’eau, en particulier pour les médicaments de classe Ⅱ et Ⅳ du système de classification biopharmaceutique (BCS) 5, 6. En outre, il a été signalé que Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) présentait une forte amélioration de la sécrétion de chylomicrons à faible concentration et amélioration du transport lymphatique intestinal 25, ce qui améliorerait encore la capacité d’absorption des médicaments.

En tant que surfactant, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) montre une capacité exceptionnelle à augmenter l’absorption des médicaments à travers différentes barrières biologiques. Par exemple, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) a été utilisé pour fabriquer des nanocristaux de répaglinide pour améliorer la solubilité de saturation et la biodisponibilité orale jusqu’à 25,7 fois et 15,0 fois par rapport au médicament libre, respectivement 26. Dans les études de transport en chambre, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut améliorer la perméation du médicament dans le tissu colique 27. En outre, l’influence de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) sur la capacité d’absorption intestinale de l’icariside Ⅱ a été étudiée dans un modèle monocouche Caco-2 et un modèle de perfusion intestinale de rat à quatre sites. Dans le modèle monocouche Caco-2, la valeur des coefficients de perméabilité apparente de l’icariside Ⅱ a été augmentée et le rapport d’efflux a été remarquablement réduit en raison de l’effet de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS). L’enquête sur le modèle de perfusion intestinale de rat à quatre sites a en outre montré une augmentation significative de la perméabilité de l’icariside Ⅱ dans l’iléon et le côlon 28. Des résultats similaires ont été trouvés dans le modèle monocouche Caco-2 avec rhodamine123 (Rh123) en présence de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) 29. Fait intéressant, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut également agir comme agent porogène dans la fabrication de nanoparticules avec une efficacité d’encapsulation de médicaments élevée, une petite taille de particules et une libération rapide de médicaments 30. En outre, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut être utilisé comme émulsifiant ou stabilisant de surface pour la préparation de formulations médicamenteuses comme hydrophobe. la partie peut piéger le médicament hydrophobe et la partie hydrophile peut stabiliser les formulations.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) comme inhibiteur de la P-gp pour surmonter la MDR

La résistance aux médicaments des cellules cancéreuses peut restreindre l’efficacité thérapeutique d’un traitement chimiothérapeutique. En tant que transporteur membranaire dépendant de l’ATP, la P-gp a été l’une des principales causes de MDR. Il peut pomper les médicaments du substrat de la P-gp pour diminuer l’accumulation intracellulaire de médicaments, réduisant ainsi l’effet cytotoxique des médicaments chimiothérapeutiques dans le traitement du cancer résistant aux médicaments. Au cours des dernières décennies, il y a eu un intérêt continu pour combiner des médicaments de substrat de P-gp avec un inhibiteur ou un polymère avec une capacité d’inhibition de la P-gp dans des formulations pour surmonter la MDR 31. Rh123, un substrat de la P-gp, est généralement utilisé comme médicament modèle pour étudier la rétention intracellulaire du médicament dans les cellules tumorales MDR. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut augmenter considérablement l’accumulation intracellulaire de Rh123 dans les cellules tumorales pharmacorésistantes par rapport au Rh123 libre, ce qui a été mis en évidence par la cytométrie en flux et l’analyse au microscope confocal 32. Il semble que Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut effectivement inhiber l’activité de la P-gp pour surmonter MDR.

Étant donné que le transporteur d’efflux P-gp est dépendant de l’ATP, l’épuisement de l’ATP joue un rôle très important pour surmonter la MDR. L’effet d’inversion MDR de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) est principalement attribué à sa double action, l’inhibition du complexe respiratoire mitochondrial Ⅱ pour court-circuiter l’approvisionnement en ATP et la suppression de l’activité P-gp ATPase induite par le substrat pour bloquer l’utilisation de l’ATP 20, 21, 33, 34.

Le complexe respiratoire mitochondrial Ⅱ, également appelé succinate déshydrogénase, joue un rôle important dans le transport d’électrons mitochondrial, qui est une partie essentielle du cycle de l’acide tricarboxylique ainsi que de la chaîne respiratoire mitochondriale 35. Le Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut se lier au complexe respiratoire mitochondrial Ⅱ et induire des dysfonctionnement mitochondrial, entraînant un épuisement significatif de l’énergie intracellulaire 20, 36. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut s’accumuler dans les mitochondries et inhiber l’activité du complexe Ⅱ, et par conséquent perturber le transfert d’électrons et activer le canal calcique, ce qui entraînerait une surcharge en calcium et un dysfonctionnement qui en découlerait des mitochondries. Le dysfonctionnement mitochondrial est caractérisé par un effet dissipateur sur le potentiel de la membrane mitochondriale, une diminution du niveau d’ATP et une augmentation de la génération d’espèces réactives de l’oxygène (ROS) 37. En outre, la capacité de ciblage mitochondrial de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut accélérer le dysfonctionnement mitochondrial 32, 38. P-gp induite par le substrat La suppression de l’activité ATPase est un autre mécanisme permettant à Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) de diminuer l’efflux du médicament 21. L’activité ATPase peut être stimulée par la liaison du substrat aux régions transmembranaires de la P-gp 39. Par la suite, l’ATP est transformé en adénosine diphosphate (ADP) pour l’apport énergétique de efflux de drogue. Contrairement à l’inhibiteur classique de la P-gp vérapamil, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) n’est pas un substrat de la P-gp et ne montre aucun effet d’inhibition compétitif de la liaison au substrat. La fonction de blocage stérique du site de liaison et / ou la modulation allostérique de la P-gp semblent être le mécanisme d’inhibition de l’ATPase.

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) comme agent anticancéreux sélectif pour des effets antitumoraux synergiques

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut induire l’apoptose et présente des effets cytotoxiques sélectifs contre les cellules cancéreuses, qui peuvent être combinés avec des médicaments chimiothérapeutiques pour réduire les effets secondaires et augmenter l’efficacité du traitement. Il y a une réponse différente significative sur les cellules mammaires immortalisées normales et les cellules cancéreuses après le traitement Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS). Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut déclencher les voies de signalisation apoptotiques et induire l’arrêt du cycle cellulaire G1 / S dans les cellules cancéreuses du sein MCF-7 et MDA-MB-231, mais aucun effet remarquable sur les cellules non tumorigènes MCF-10A et MCF-12F 40. Par coïncidence, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut induire l’apoptose sur les cellules T leucémie lymphocytaire aiguë des cellules Jurkat clone E6-1, mais pas sur les lymphocytes du sang périphérique humain. L’apoptose a été mise en évidence par une fragmentation accrue de l’ADN nucléaire, un meilleur arrêt du cycle cellulaire et une réduction du potentiel de membrane mitochondriale 41. Les mécanismes d’apoptose sélective des cellules cancéreuses médiées par Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) sont compliqués et peuvent être énumérés comme suit:

 

 

Inducteur ROS

Semblable au succinate d’α-tocophéryle (α-TOS), Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut induire l’apoptose des cellules cancéreuses par la destruction et l’inhibition du complexe respiratoire mitochondrial Ⅱ 33, 41. La perturbation ultérieure de la chaîne de transfert d’électrons peut favoriser la génération 20 de ROS. Le ROS intracellulaire intensifié, un médiateur de l’apoptose, peut induire des dommages à l’ADN et l’oxydation des lipides, des protéines et des enzymes, conduisant à la destruction des cellules 42. En outre, il a été démontré que le mécanisme d’apoptose médiée par ROS était corrélé à l’activité anticancéreuse sélective car les cellules tumorales pourraient être plus sensible aux ROS que les cellules normales 43-45. Comparé au TOS, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) a présenté une capacité de génération ROS améliorée 46.

Régulation à la baisse des protéines anti-apoptotiques

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut inhiber la phosphorylation de la protéine kinase B (PKB ou AKT), puis réguler à la baisse les protéines anti-apoptotiques Survivin et Bcl-2, qui peuvent induire l’activation des caspases-3 et -7 pour la mort cellulaire programmée dépendante de la caspase 40. Parallèlement, une mort cellulaire programmée indépendante de la caspase et un arrêt du cycle cellulaire en phase G1 / S se sont également produits 40, 41. La survivine et la Bcl-2 sont généralement surexprimées dans la plupart des cellules cancéreuses alors qu’elles sont remarquablement réduites dans les cellules normales 47. Cela peut être la principale raison de la cytotoxicité sélective de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS).

Dommages à l’ADN

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut induire des dommages à l’ADN dépendants et indépendants de la caspase. Ce type de dommages à l’ADN a été observé dans les cellules LNCaP positives aux récepteurs androgènes (AR +), mais pas dans les cellules AR-DU145 et PC3, qui étaient liées au microenvironnement cellulaire 48.

Conjugué Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX

La doxorubicine (DOX) est un substrat de la P-gp et un médicament anticancéreux à large spectre. Cependant, la pharmacorésistance acquise de la DOX est un obstacle à ses applications cliniques dans les progrès de la thérapie anticancéreuse. Bao et coll. 23 ont développé un promédicament lié à une base de Schiff sensible au pH, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CH = N-DOX (également appelé TD), en conjuguant DOX avec Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) pour surmonter la MDR. Ce promédicament peut s’auto-assembler en micelles stables dans des conditions physiologiques et réaliser un ciblage tumoral in vivo et une longue circulation sanguine en introduisant un lipide PEGylé. C’était la première fois de fournir un moyen «moléculaire économique» de lutter contre la tumeur car le système combinait le ciblage de la tumeur à partir du récepteur de l’intégrine ligand peptide cyclique RGD (cRGD), propriété de longue circulation du lipide PEGylé, surmontant MDR du matériau Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et libération sensible aux stimuli de l’éditeur de liens basé sur Schiff. Les micelles hybrides formulées présentaient un profil de libération de médicament sensible au pH et un changement évident de la taille des particules dans un tampon pH 5,0 qui simulait l’environnement acide endo / lysosomal. Il a également démontré une augmentation de l’absorption de DOX par cytométrie en flux et analyse au microscope confocal, et une rétention améliorée grâce à la pharmacocinétique in vivo par rapport au médicament libre. DOX a présenté une bonne rétention dans les cellules MCF-7 sensibles aux médicaments pendant l’incubation. Au contraire, le médicament libre a montré une très faible teneur en DOX et une rétention remarquablement réduite dans les cellules MCF-7 / ADR même avec un temps d’incubation prolongé. Les inhibiteurs de la P-gp du vérapamil et du Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peuvent augmenter l’accumulation de médicament dans les cellules MCF-7 / ADR. Les micelles de promédicaments ont atteint la même tendance d’absorption et de rétention de médicaments avec le mélange de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et DOX dans des cellules MCF-7 / ADR. Il semble que le Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) rapidement dissocié des micelles internalisées puisse inhiber l’activité de la P-gp et retenir la DOX pour une cytotoxicité ultérieure contre les tumeurs MDR. La cytotoxicité et l’apoptose améliorées ont été induites par les micelles hybrides dans les cellules MCF-7 / ADR par rapport à la DOX libre car les concentrations inhibitrices demi-maximales (IC50) des micelles hybrides étaient 95 fois inférieures à celles du médicament libre après 72 h d’incubation. Le mécanisme de l’efficacité antitumorale a été étudié plus en détail par l’analyse de la production intracellulaire de ROS, le changement du potentiel de membrane mitochondriale (ΔΨm) et le niveau d’ATP intracellulaire (Figure Figure 22B). L’accumulation de ROS, la diminution du potentiel de membrane mitochondriale et la diminution de la production d’ATP à partir des micelles hybrides peuvent contribuer à l’inhibition de la P-gp par Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) en coupant l’approvisionnement en énergie des “ centrales électriques cellulaires ” des mitochondries. Le promédicament a présenté une inhibition significative de la croissance sur la tumeur MCF-7 / ADR (figure Figure 22C) et également une inhibition de la croissance tumorale / métastase sur le mélanome murin B16F10 et l’hépatocarcinome H22 avec cRGD décoré sur les micelles hybrides. Il a fourni une plate-forme de promédicaments sûre et simple pour alléger le fardeau du système d’administration et améliorer l’efficacité thérapeutique de la nanomédecine grâce à la conception rationnelle de promédicaments pour un traitement efficace du cancer.

Certains autres promédicaments Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX ont également été conçus et fabriqués 55-57. Le groupe 55 de Feng a développé le promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX en conjuguant directement le Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) modifié à l’anhydride succinique avec DOX. Le promédicament a montré une absorption cellulaire et une cytotoxicité améliorées. Par rapport au médicament libre, 4,5 et 24 fois la demi-vie (t1 / 2) et l’aire sous la courbe (AUC) ont été trouvés dans le promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX, respectivement. Le conjugué Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX-acide folique (Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX-FOL) a ensuite été introduit pour une chimiothérapie ciblée avec des effets thérapeutiques plus élevés et moins d’effets secondaires 56. De plus, le promédicament de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX peut également être appliqué pour conditionner le médicament à des fins combinatoires. thérapie. Hou et coll. 57 ont construit un promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX sensible à l’acide en synthétisant d’abord un DOX modifié à l’anhydride cis-aconitique sensible au pH, puis en le conjuguant avec Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS). Le promédicament peut s’auto-assembler en nanoparticules. Le photosensibilisateur chlorine e6 (Ce6) a été chargé dans ces nanoparticules de promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-DOX pour l’imagerie par fluorescence proche infrarouge et la combinaison de chimiothérapie et de thérapie photodynamique contre la tumeur. Les nanoparticules présentaient des caractéristiques de libération de DOX et de Ce6 sensibles au pH, ce qui était causé par le linker sensible à l’acide entre Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et DOX. Il a également démontré des effets synergiques sur l’absorption cellulaire, l’apoptose des cellules cancéreuses et une suppression significative de la croissance dans le cancer du poumon non à petites cellules (A549).

 

 

Conjugué Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-PTX

Le paclitaxel (PTX) est un médicament de classe BCS Ⅳ avec une solubilité et une perméabilité médiocres ainsi qu’un substrat de la P-gp, ce qui entrave l’administration efficace du médicament et la thérapie tumorale MDR. Le groupe 58 de Zhang a synthétisé un promédicament sensible à l’oxydoréduction Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX, qui pourrait être rapidement dissocié dans un environnement redox intracellulaire (concentration élevée de GSH) pour libérer PTX pour la cytotoxicité contre la tumeur et l’ingrédient actif Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) pour l’inhibition de la P-gp. Le promédicament peut s’auto-assembler en micelles stables et réaliser le ciblage passif de la tumeur grâce à l’effet amélioré de perméation et de rétention (EPR). Comparé au promédicament PTX conjugué par liaison ester non réactif Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX a montré une meilleure stabilité et une libération de médicament soutenue in vitro déclenchée par un environnement réducteur intracellulaire. L’augmentation de la stabilité des micelles Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX peut être attribuée au lieur de sulfures doux entre Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et PTX par rapport aux deux seuls lieurs de carbone de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX. Par rapport à la formulation clinique de Taxol® et Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX, les micelles Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX ont présenté une accumulation intracellulaire accrue de PTX pour les cellules A2780 / T résistantes aux médicaments, qui peut être causée par le Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) rapidement dissocié du redox -prodrogue sensible. Rh123 a été utilisé comme médicament modèle de substrat de la P-gp pour évaluer la rétention de médicament dans la tumeur MDR. Lorsque les cellules traitées avec du vérapamil ou des promédicaments, l’intensité de fluorescence de Rh123 a été augmentée par rapport à Rh123 libre. En particulier, une intensité de fluorescence beaucoup plus élevée a été présentée dans Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-SS-PTX par rapport à Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX, ce qui a en outre confirmé la propriété d’inhibition de la P-gp de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) dissocié. Comme prévu, cette micelle de promédicament fonctionnelle a augmenté la cytotoxicité de PTX dans les cellules A2780 / T. Comparé au promédicament non clivable Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-CC-PTX et au Taxol®, le promédicament répondant aux stimuli a réduit la CI50 et augmenté l’apoptose / nécrose de la tumeur MDR. L’évaluation in vivo a en outre démontré le potentiel de cette micelle de promédicament sur le traitement du cancer en tant que l’ASC accrue, la t1 / 2 étendue, la distribution améliorée du médicament dans la tumeur et une inhibition significative de la croissance tumorale avec des effets secondaires réduits.

Conjugué Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatine

Le cisplatine est largement utilisé dans les cancers du poumon testiculaire, ovarien, cervical, de la tête et du cou et non à petites cellules. Cependant, l’application clinique est limitée pour la faible solubilité, la néphrotoxicité, la neurotoxicité périphérique sévère, la résistance aux médicaments inhérente et acquise 59. Le groupe 60 de Feng a développé le promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatine pour améliorer l’hydrosolubilité et réduire la neurotoxicité du cisplatine. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatine peut s’auto-assembler en micelles avec une capacité de chargement de médicament élevée. L’absorption cellulaire et la cytotoxicité plus élevées contre les cellules d’hépatocarcinome HepG2 ont été trouvées dans le promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatine par rapport au médicament libre. Les micelles de promédicament ont également montré des effets neuroprotecteurs significatifs avec une valeur IC50 plus élevée pour les cellules de type neuroblaste SH-SY5Y par rapport au cisplatine libre. En outre, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) est un puissant agent anticancéreux dans le traitement du cancer du sein avec un niveau élevé d’expression du récepteur 2 du facteur de croissance épidermique humain (HER2) 61. Il peut être lié à l’effet inhibiteur du complexe respiratoire mitochondrial Ⅱ et à la génération de ROS qui en résulte, résultant en une apoptose cellulaire via la voie de signalisation 33 de la tyrosine kinase du récepteur HER2. Mi et ses collaborateurs 62 ont développé un système de délivrance ciblée de nanoparticules de promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatine pour la co-administration de cisplatine, docétaxel (DTX) et Herceptin pour une bonne inhibition tumorale dans HER2 cancers du sein surexprimés. Poly (acide lactique) (PLA) -Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-COOH et Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-cisplatine ont été mélangés pour fabriquer des nanoparticules pour le traitement multimodal du cancer du sein. Les nanoparticules chargées à plusieurs médicaments présentaient une valeur IC50 beaucoup plus faible pour les cellules SK-BR-3 avec une expression élevée de HER2 par rapport au mélange de médicaments libres.

Conjugué Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU

Le groupe 63, 64 de Liu a développé des nanoparticules multifonctionnelles pour la co-administration du médicament hydrophobe PTX et du médicament hydrophile 5-fluorouracile (5-FU) pour surmonter la MDR. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU a été synthétisé en conjuguant simplement Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) succinoylé avec 5-FU. Les nanoparticules, composées de promédicament Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU et de PTX, ont montré une cytotoxicité accrue contre la tumeur MDR par rapport au traitement d’agent individuel 64. Ils ont développé des nanoémulsions avec PTX-Vitamine E et Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS)-5-FU promédicament. Les nanoémulsions avec la co-administration de médicaments ont montré un effet synergique de surmonter la résistance au PTX dans la lignée cellulaire de carcinome épidermique humain KB-8-5 63. L’activité anticancéreuse efficace était le résultat de l’effet d’inhibition de la P-gp de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et de l’effet synergique de PTX et 5-FU qui peut simultanément cibler diverses voies de signalisation pour tuer le cancer.

Ciblage du Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) conjugué au ligand

RGD a été appliqué comme ligand de ciblage potentiel dans le traitement du cancer pour les tumeurs avec surexpression des récepteurs de l’intégrine αvβ3. Le groupe 112 de Li a formulé PTX et Survivin shRNA co-chargé des nanoparticules ciblées en mélangeant Pluronic P85-polyéthylèneimine, Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et iRGD-Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) pour surmonter la résistance aux médicaments (Figure Figure 55A). Les nanoparticules présentaient une absorption cellulaire accrue, un effet d’interférence ARN et une cytotoxicité à la fois sur les cellules A549 et A549 / T. Il a en outre été démontré que les nanoparticules ciblées présentaient des effets antitumoraux significatifs du système de co-administration par rapport au Taxol®. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) conjugué RGD a également été utilisé pour préparer les micelles ciblées en mélangeant avec de l’oligosaccharide de chitosane greffé succinate de vitamine E (VES), qui présentait une bonne inhibition de la croissance sur la tumeur du glioblastome humain (U87MG) 113. Le peptide tLyp-1 a une forte affinité pour récepteur de la neuropiline-1 (NRP-1). Il peut également être utilisé comme peptide de ciblage pour décorer à la surface des nanoparticules sous forme de NRP-1 surexprimé sur les cellules tumorales et d’angiogenèse. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) a d’abord été conjugué avec le peptide tLyP-1, puis mélangé avec PLA-Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) et Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) conjugué à Ce6 pour fabriquer des nanoparticules chargées de DOX via une méthode de nanoprécipitation. Les nanoparticules résultantes peuvent améliorer l’extravasation vasculaire et améliorer la pénétration et l’accumulation de médicaments dans la tumeur pour les effets antitumoraux synergiques de la thérapie chimio-photodynamique combinatoire (Figure Figure 55B) 114. En outre, une sorte de micelles théranostiques de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) conjugué à la transferrine a été appliquée pour la co-délivrance ciblée de DTX et de clusters d’or pour l’imagerie et la thérapie simultanées du cancer. Les micelles présentaient une cytotoxicité améliorée avec des valeurs IC50 71,7 fois et 4,7 fois inférieures dans les cellules cancéreuses du sein MDA-MB-231-luc avec surexpression des récepteurs de la transferrine par rapport à Taxotere® et aux micelles non ciblées, respectivement. L’imagerie in vivo et l’efficacité antitumorale ont en outre été mises en évidence chez les souris porteuses de tumeurs 115.

Formulations à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) non modifiées

Selon les propriétés de base mentionnées ci-dessus, le Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) non modifié peut être utilisé comme matériau multifonctionnel dans un système d’administration de médicament. Ces fonctions peuvent être résumées comme le dépassement de la MDR, l’amélioration de la biodisponibilité des médicaments par voie orale et la promotion de la perméation des médicaments.

Formulations à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) pour surmonter la MDR

Des recherches scientifiques ont validé que Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut être utilisé comme support de médicament et inhibiteur de la P-gp dans la fabrication de nanomédicaments pour l’inversion de la MDR dans le traitement du cancer (tableau Tableau 33). Gao et coll. 120 ont développé les nanosuspensions PTX stabilisées Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS), qui présentaient une dose létale médiane (DL50) de toxicité aiguë et une pharmacocinétique améliorée par rapport à celle de l’injection commercialisée. Les nanosuspensions ont en outre été évaluées sur des cellules cancéreuses du poumon humain H460 surexprimées par la P-gp (H460 / RT) avec une cytotoxicité significativement élevée et une augmentation de 5 fois du taux d’inhibition de la tumeur par rapport à la solution mixte de PTX et de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) après i.v. administration 121. Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) a également été utilisé pour préparer des nanoémulsions PTX pour surmonter la résistance aux médicaments dans les cellules MCF-7 / ADR. Les nanoémulsions ont présenté une inhibition significative de la P-gp et un taux d’inhibition de la tumeur de 94% (Figure Figure 66A) 18.

Formulations à base de Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) pour favoriser la perméation des médicaments

Kolliphor TPGS (vitamin E TPGS, E vitamini TPGS) peut améliorer la perméation des médicaments à travers les barrières physiologiques telles que la peau ou la cornée. Il peut être appliqué pour construire de nombreuses formulations pour l’administration transdermique de médicaments et la thérapie des maladies oculaires.