ReviewVitamin E TPGS as a molecular biomaterial for drug delivery
Introduction
d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) (as shown in Scheme 1) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG). As such it has advantages of PEG and Vitamin E in application of various drug delivery device, including extending the half-life of the drug in plasma and enhancing the cellular uptake of the drug. Typically, the molecular weight of TPGS with PEG1000 segment is 1513. TPGS has amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with a hydrophile-lipophile balance (HLB) value of 13.2 and a critical micelle concentration (CMC) of 0.02% w/w [1]. TPGS safety issue has been investigated in details and it has been reported that the acute oral median lethal dose (LD50), which is defined as the quantity of an agent that will kill 50 percent of the test subjects within a designated period, is >/7 g/kg for young adult rats of both sexes [2]. US FDA has approved TPGS as a safe pharmaceutical adjuvant used in drug formulation.
In recent years TPGS has been intensively applied in developing the various drug delivery systems. TPGS has been used as an absorption enhancer, emulsifier, solublizer, additive, permeation enhancer and stabilizer [3], [4]. TPGS has also been served as the excipient for overcoming multidrug resistance (MDR) and inhibitor of P-glycoprotein (P-gp) for increasing the oral bioavailability of anticancer drugs [4], [5], [6], [7]. TPGS has also been applied for prodrug design for enhanced chemotherapy [8], [9]. Feng's group has been focused in the past decade on various applications of TPGS in nanomedicine, including TPGS-based prodrugs, micelles, liposomes, TPGS-emulsified PLGA nanoparticles and nanoparticles of TPGS-based copolymers, which can significantly enhance the solubility, permeability and stability of the formulated drug and realize sustained, controlled and targeted drug delivery. TPGS has been proved to be an efficient emulsifier for synthesis of nanoparticles of biodegradable polymers, resulting in high drug encapsulation efficiency, high cellular uptake in vitro and high therapeutic effects in vivo [10], [11], [12]. For example, TPGS may have more than 77 times higher emulsification efficiency compared with the traditional emulsifier polyvinyl alcohol (PVA), i.e. to produce the same amount of polymeric nanoparticles by the single emulsion method, the needed TPGS amount can be only 1/77 than that of PVA as the emulsifier used in the process. TPGS-emulsified nanoparticles or TPGS-based nanoparticles have been found to increase the cell uptake efficiency on Caco-2, HT-29, MCF-7, C6 glioma cells and thus enhance cancer cell cytotoxicity. The TPGS-based nanoparticles have been further found in resulting in a more desired pharmacokinetics of entrapped drug in vivo, which could significantly extend the half-life of the formulated drug in the plasma. Feng's group has realized 168 h effective paclitaxel (PTX) chemotherapy by the TPGS-emulsified PLGA nanoparticles formulation in comparison with Taxol® of only 22 h effective chemotherapy at the same 10 mg/kg body weight of rats. Moreover, they have found that 400% higher drug tolerance can be achieved, which could result in 360% AUC as a quantitative measurement of the in vivo chemotherapeutical effects. It means that the animal immune system failed to recognize and thus eliminate the nanoparticles. They proved in vivo the feasibility of nanomedicine, which had been one of the two major concerns for the newly emerging area nanomedicine as future medicine. They then further confirmed such advantages of nanomedicine that the PLA-TPGS nanoparticle formulation of PTX and docetaxel (DOC) can realize 336 h and 360 h sustained effective chemotherapy respectively in comparison 23 h chemotherapy of Taxotere® at the same 10 mg/kg body weight for rats. Also, a more desirable biodistribution of the drug could be resulted with less drug in kidney, liver, heart and more in blood and lung. Oral delivery and drug delivery across the blood–brain barrier can also be achieved by further development of the nanoparticle technology with enhanced size and size distribution, surface functionalization, and copolymer synthesis [13], [14], [15].
In this review, we discuss in details the advantages of the various TPGS-based drug delivery systems such as prodrugs, micelles, liposomes, TPGS-emulsified PLGA nanoparticles and nanoparticles of TPGS copolymers such as PLA-TPGS, TPGS-COOH, PCL-TPGS, and so on.
Section snippets
TPGS as prodrug carrier
A prodrug is a pharmaceutical agent which is administered in an inactive form (say conjugated to a polymer) and then bioactivated (say released from the drug-polymer conjugate) into active metabolites in vivo. The rationale behind a prodrug is generally to enhance the pharmacokinetics of a drug, i.e. to optimize the process of absorption, distribution, metabolism, and excretion (ADME). Prodrugs are usually designed to improve oral bioavailability of the drug with poor absorption from the
TPGS-based micelles
TPGS has micellar properties and can formulate micelles for delivery of drug or imaging agent [28]. TPGS micelles were also used to encapsulate other functional materials like carbon nanotubes [29], fullerenes or iron oxide [30]. It has been proved that TPGS was a more effective dispersing agent of multi-wall and single-wall carbon nanotubes than the commonly used Triton X-100 in water. C60 was also solublized in TPGS aqueous solution from fullerene. Highly ordered asymmetric nanoparticles,
TPGS-based liposomes
TPGS can be used as a surfactant and/or component in liposomal formulation, which may bring some advantages for the sustained and controlled drug delivery [43]. Muthu et al. prepared nano-sized non-coated liposomes, PEG-DSPE coated liposomes and TPGS coated liposomes with DOC as the anticancer agent [44]. TPGS coated liposomes showed maximum DOC encapsulation efficiency (64%), higher cellular uptake and cytotoxicity (84.0% decrease in the IC50 value compared with that of Taxotere®). The
TPGS-emulsified nanoparticles
TPGS can be used as an emulsifier or an ideal coating molecule which can achieve high drug EE (up to 100%) and higher cellular uptake of the nanoparticles, and thus high therapeutic effects compared with PVA emulsified nanoparticles [14]. Feng's group did lots of works in this field and showed many impressive results [13], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67]. They applied TPGS as a surfactant to fabricate PTX-loaded PLGA nanospheres in the solvent evaporation/extraction
TPGS as additive for nanoparticles formulation
TPGS can be a matrix of micro-/nanoparticles after blended TPGS with PLA, PLGA, poly (caprolactone) for anticancer drug, pacltiaxel, diphtheria toxoid and others, fabricated by dialysis, modified solvent extraction/evaporation, or spray drying method with increased encapsulation efficiency and sustained release [56], [60], [62], [83], [84]. TPGS as additive increased the drug encapsulation efficiency up to 75.9% compared to 69.0% for particles without TPGS for 4.2% drug loading. 90.1%
Polymer synthesis
Zhang et al. synthesized PLA-TPGS copolymers in 2006 and applied this copolymer in anticancer drugs delivery including paclitaxel, DOX and also protein BSA. The copolymers were synthesized with various lactide and TPGS ratios by ring opening polymerization with stannous octoate as catalyst (Scheme 3) [12]. Molecular structure of the copolymer was characterized by FTIR spectrophotometer and 1H NMR in CDCl3. The weight-averaged molecular weight and molecular weight distribution were determined by
Targeting strategies
Although TPGS itself cannot realize targeting effect but it can be used as the linking agent for realizing different targeting effect in nanoparticles fabrication. Foliate was widely studied on targeting drug delivery because most of tumor cells overexpressed foliate receptor on the tumor cell surface compared with normal cells. Foliate has small molecular weight and is not easy to apply as matrix of nanoparticles or without effect after directly added to drug solution. There are two ways for
Advantages of the PLA-TPGS series copolymer
PLA-TPGS has been shows as potential candidate for drug delivery carrier as exhibited above. It can be developed to deliver anticancer reagent such as pacltiaxel, DOC, DOX, protein BSA, and imaging reagent QDs and iron nanoparticles and so on with higher encapsulation efficiency compared with commonly used PLGA. The amphiphilic structure of the polymer can promote nanoparticles increased the cellular uptake of NPs and cell cytotoxicity of payload, extended much longer circulation time in vivo,
Acknowledgments
The work was financially supported jointly by National Basic Research Program of China (973 Program, 2012CB932500) and the Singapore-China Collaborative Grant, A*STAR, Singapore (R-398-000-077-305, PI: SS Feng) and NUS FRC R-397-000-136-731 (Co-PI: SS Feng).
References (121)
- et al.
Enhanced oral paclitaxel absorption with vitamin E-TPGS: effect on solubility and permeability in vitro, in situ and in vivo
Eur J Pharm Sci
(2005) - et al.
Doxorubicin conjugated to D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS): conjugation chemistry, characterization, in vitro and in vivo evaluation
Biomaterials
(2008) - et al.
Superparamagnetic iron oxide - loaded poly (lactic acid)-D-alpha-tocopherol polyethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agent
Biomaterials
(2010) - et al.
Nanoparticles of poly(lactide)/vitamin E TPGS copolymer for cancer chemotherapy: synthesis, formulation, characterization and in vitro drug release
Biomaterials
(2006) - et al.
Water soluble polymers in tumor targeted delivery
J Control Release
(2001) - et al.
HPMA copolymer-anticancer drug conjugates: design, activity, and mechanism of action
Eur J Pharm Biopharm
(2000) - et al.
Properties of HPMA copolymer-doxorubicin conjugates with pH-controlled activation: effect of polymer chain modification
J Control Release
(2006) - et al.
Effective drug delivery by PEGylated drug conjugates
Adv Drug Deliver Rev
(2003) - et al.
Synthesis and evaluation of water-soluble paclitaxel prodrugs
Bioorg Med Chem Lett
(2002) PEG drugs: an overview
J Control Release
(2001)
Investigation of the micellar properties of the tocopheryl polyethylene glycol succinate surfactants TPGS 400 and TPGS 1000 by steady state fluorometry
J Colloid Interf Sci
Efficient dispersing and shortening of super-growth carbon nanotubes by ultrasonic treatment with ceramic balls and surfactants
Adv Powder Technol
Tocopheryl polyethylene glycol succinate as a safe, antioxidant surfactant for processing carbon nanotubes and fullerenes
Carbon
Vitamin E (D-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles-superparamagnetic iron oxide nanoparticles for enhanced thermotherapy and MRI
Biomaterials
Mixed micelles made of poly(ethylene glycol)-phosphatidylethanolamine conjugate and D-alpha-tocopheryl polyethylene glycol 1000 succinate as pharmaceutical nanocarriers for camptothecin
Int J Pharm
Polyethylene glycol-phosphatidylethanolamine conjugate (PEG-PE)-based mixed micelles: some properties, loading with paclitaxel, and modulation of P-glycoprotein-mediated efflux
Int J Pharm
Design and evaluation of micellar nanocarriers for 17-allyamino-17-demethoxygeldanamycin (17-AAG)
Int J Pharm
Multi-drug delivery to tumor cells via micellar nanocarriers
Int J Pharm
Preparation and characterization of Pluronic/TPGS mixed micelles for solubilization camptothecin
Colloids Surf B
Preparation and properties of hydroxycamptothecin-loaded nanoparticles made of amphiphilic copolymer and normal polymer
J Colloid Interf Sci
Combination of Pluronic/Vitamin E TPGS as a potential inhibitor of drug precipitation
Int J Pharm
Formulation of Docetaxel by folic acid-conjugated D-alpha-tocopheryl polyethylene glycol succinate 2000 (Vitamin E TPGS(2k)) micelles for targeted and synergistic chemotherapy
Biomaterials
In vitro evaluation of liposomes containing bio-enhancers for the oral delivery of macromolecules
Eur J Pharm Biopharm
Vitamin E TPGS coated liposomes enhanced cellular uptake and cytotoxicity of docetaxel in brain cancer cells
Int J Pharm
Development of new lipid-based paclitaxel nanoparticles using sequential simplex optimization
Eur J Pharm Biopharm
Stability of liposomes containing bio-enhancers and tetraether lipids in simulated gastro-intestinal fluids
Int J Pharm
Effect of D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) on surfactant monolayers
Colloids Surf B
Surfactant dependent toxicity of lipid nanocapsules in HaCaT cells
Int J Pharm
Transferrin-conjugated lipid-coated PLGA nanoparticles for targeted delivery of aromatase inhibitor 7 alpha-APTADD to breast cancer cells
Int J Pharm
Factors affecting drug encapsulation and stability of lipid-polymer hybrid nanoparticles
Colloids Surf B
Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol (R))
J Control Release
A novel controlled release formulation for the anticancer drug paclitaxel (Taxol (R)): PLGA nanoparticles containing vitamin E TPGS
J Control Release
Chemotherapeutic engineering: Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in vivo
Chem Eng Sci
Enhanced oral bioavailability of paclitaxel formulated in Vitamin E-TPGS emulsified nanoparticles of biodegradable polymers: in vitro and in vivo studies
J Pharm Sci
Preparation and in vitro properties of redox-responsive polymeric nanoparticles for paclitaxel delivery
Colloids Surf B
Enhanced cellular uptake and in vivo pharmacokinetics of rapamycin-loaded cubic phase nanoparticles for cancer therapy
Acta Biomater
Application of TPGS in polymeric nanoparticulate drug delivery system
Colloids Surf B
Reversal of doxorubicin-resistance by multifunctional nanoparticles in MCF-7/ADR cells
J Control Release
Chemotherapeutic engineering: application and further development of chemical engineering principles for chemotherapy of cancer and other diseases
Chem Eng Sci
In vitro and in vivo studies on vitamin E TPGS-emulsified poly(D, L-lactic-co-glycolic acid) nanoparticles for paclitaxel formulation
Biomaterials
Novel powder formulations for controlled delivery of poorly soluble anticancer drug: application and investigation of TPGS and PEG in spray-dried particulate system
J Control Release
Effects of material hydrophobicity on physical properties of polymeric microspheres formed by double emulsion process
J Control Release
Folate-decorated poly(lactide-co-glycolide)-vitamin E TPGS nanoparticles for targeted drug delivery
Biomaterials
Nanoparticle formulation of poly(epsilon-caprolactone-co-lactide)-D-alpha-tocopheryl polyethylene glycol 1000 succinate random copolymer for cervical cancer treatment
Polymer
Transferrin-conjugated nanoparticles of poly(lactide)-D-alpha-Tocopheryl polyethylene glycol succinate diblock copolymer for targeted drug delivery across the blood-brain barrier
Biomaterials
Methoxy poly(ethylene glycol)-poly(lactide) (MPEG-PLA) nanoparticles for controlled delivery of anticancer drugs
Biomaterials
Characteristics of D-alpha-tocopheryl PEG1000 succinate for applications as an absorption enhancer in drug delivery systems
Pharm Tech
D-alpha-tocopheryl polyethylene glycol 1000 succinate. Acute toxicity, subchronic feeding, reproduction and teralogic studies in the rat
J Agric Food Chem
Vitamin E-TPGS increases absorption flux of an HIV protease inhibitor by enhancing its solubility and permeability
Pharm Res
Inhibition of P-glycoprotein by D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS)
Pharm Res
Cited by (529)
Role of micelle dynamics in enhancing cyclosporine uptake in hyaluronic acid-contact lenses for improved critical lens properties in dry eye management
2024, Colloids and Surfaces A: Physicochemical and Engineering AspectsAn injectable CS-hydrogel incorporating TPGS for cartilage repair
2024, Materials and DesignMulti-functional D-alpha-tocopheryl polyethylene glycol succinate surface modified nanocrystals improve the stability and oral bioavailability of pueraria flavonoids
2024, Journal of Drug Delivery Science and TechnologyFinding vitamin Ex<sup>‡</sup>
2024, Free Radical Biology and Medicine