Vitamin E TPGS as a molecular biomaterial for drug delivery

Abstract

d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS, or simply TPGS) 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 nanocarriers for drug delivery,  including extending the half-life of the drug in plasma and enhancing the cellular uptake of the drug. TPGS has an amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with a hydrophile/lipophile balance (HLB) value of 13.2 and a relatively low critical micelle concentration (CMC) of 0.02% w/w, which make it to be an ideal molecular biomaterial in developing various drug delivery systems, including prodrugs, micelles, liposomes and nanoparticles, which would be able to realize sustained, controlled and targeted drug delivery as well as to overcome multidrug resistance (MDR) and to promote oral drug delivery as an inhibitor of P-glycoprotein (P-gp). In this review, we briefly discuss its physicochemical and pharmaceutical properties and its wide applications in composition of the various nanocarriers for drug delivery, which we call TPGS-based drug delivery systems.

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.