Design and Development of D‒α‒Tocopheryl Polyethylene Glycol Succinate‒block‒Poly(ε-Caprolactone) (TPGS−b−PCL) Nanocarriers for Solubilization and Controlled Release of Paclitaxel

Abstract

The objective of this study was to synthesize and characterize a set of biodegradable block copolymers based on TPGS-block-poly(ε-caprolactone) (TPGS-b-PCL) and to assess their self-assembled structures as a nanodelivery system for paclitaxel (PAX). The conjugation of PCL to TPGS was hypothesized to increase the stability and the drug solubilization characteristics of TPGS micelles. TPGS-b-PCL copolymer with various PCL/TPGS ratios were synthesized via ring opening bulk polymerization of ε-caprolactone using TPGS, with different molecular weights of PEG (1–5 kDa), as initiators and stannous octoate as a catalyst. The synthesized copolymers were characterized using 1H NMR, GPC, FTIR, XRD, and DSC. Assembly of block copolymers was achieved via the cosolvent evaporation method. The self-assembled structures were characterized for their size, polydispersity, and CMC using dynamic light scattering (DLS) technique. The results from the spectroscopic and thermal analyses confirmed the successful synthesis of the copolymers. Only copolymers that consisted of TPGS with PEG molecular weights ≥ 2000 Da were able to self-assemble and form nanocarriers of ≤200 nm in diameter. Moreover, TPGS2000-b-PCL4000, TPGS3500-b-PCL7000, and TPGS5000-b-PCL15000 micelles enhanced the aqueous solubility of PAX from 0.3 µg/mL up to 88.4 ug/mL in TPGS5000-b-PCL15000. Of the abovementioned micellar formulations, TPGS5000-b-PCL15000 showed the slowest in vitro release of PAX. Specifically, the PAX-loaded TPGS5000-b-PCL15000 micellar formulation showed less than 10% drug release within the first 12 h, and around 36% cumulative drug release within 72 h compared to 61% and 100% PAX release, respectively, from the commercially available formulation (Ebetaxel®) at the same time points. Our results point to a great potential for TPGS-b-PCL micelles to efficiently solubilize and control the release of PAX.

Synthesis and Physicochemical Characterization of Naringeninand Gallic Acid-Loaded Polymeric Micelles for Cancer Drug Delivery

“…A previous study reported that naringenin exhibited absorption peaks of O-H stretching vibration at 3285 cm -1 and C=O stretching vibration at 1629 cm -1 (29). PEG and TPGS were shown to exhibit hydroxyl groups at 3417 cm -1 and 3452-3454 cm -1 , respectively (11,30). The characteristics band for the C=O stretching vibration of carbonyl group appeared at 1630 cm -1 for PEG (30) and at 1737-1738 cm -1 for TPGS (11).…”

“…Drug encapsulation within micelles core can be achieved through electrostatic, physical or chemical interactions (5). Different types of co-polymer such as poly(ethylene glycol) (PEG), poly(ε-caprolactone) (PCL), and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) have been studied in the formulation of cancer drug-loaded PMs (10,11). It is noteworthy that PMs are able to enhance drug bioavalability and biodistribution (9).…”

“…However, the physicochemical properties of NAR or GA in combination with TPGS and PEG in the form of polymeric micelles are still unknown. The presence of TPGS is expected to enhance nanocarrier stability and act as P-glycoprotein inhibitors whereas the PEG helps prolong drug circulation in the plasma (11,23). Thus, this study was conducted to synthesize the NAR and GA PMs using TPGS and PEG and characterize some of their physicochemical properties for potential use as new cancer nano-drug delivery systems.…”

Polymeric capsules and micelles as promising carriers of anticancer drugs

“…7 Self-assembled nanocarriers composed of D-αtocopheryl poly(ethylene glycol) succinate-block-poly(εcaprolactone) (TPGS-b-PCL) and loaded with paclitaxel owe their properties to PEG, which extends their circulation time, and vitamin E, that enhances the cellular uptake of the medication. 54 The TPGS, which is a derivative of the natural vitamin E (α-tocopherol) conjugated with PEG, was also used as a component for the production of micelles containing docetaxel. 55 Among the advanced delivery systems, tested both in vitro and in vivo, one can mention pH-sensitive, multidrug (α-tocopherol and doxorubicin) grafted O-carboxymethyl chitosan polymeric micelles with chemically conjugated targeting ligand (anti-HER2/neu peptide-PEG).…”

A pH-Responsive Zwitterionic Polyurethane Prodrug as Drug Delivery System for Enhanced Cancer Therapy

“…Currently, most conventional chemotherapeutic agents (e.g., Adriamycin (DOX), methotrexate, and camptothecin) have serious disadvantages that need to be addressed, such as low selectivity, low water solubility, substantial side effects, and short circulation time in the body [ 2 , 3 ]. To overcome these problems, scientists have developed a range of nanocarriers, such as nanoparticles, liposomes, nanogels and micelles through nanotechnology [ 4 , 5 , 6 , 7 , 8 ], such as nanocarrier-based polymer prodrugs. The hydrophobic segments of the polymer are linked to the hydrophobic drug by breakable chemical bonds to form the core of the micelle, and the hydrophilic segments form the micelle shell, providing good stability to the drug and prolonging the circulation time in vivo.…”