Core–Shell–Corona Micelle Stabilized by Reversible Cross‐Linkage for Intracellular Drug Delivery

Abstract

Reversibly cross-linked core-shell-corona micelles based on a triblock copolymer composed of poly(aliphatic ester), polyphosphoester, and poly(ethylene glycol) are reported. The triblock copolymer is synthesized through consecutive ring-opening polymerization of ε-caprolactone and 2,4-dinitrophenylthioethyl ethylene phosphate, followed by conjugation of poly(ethylene glycol). After deprotection under mild conditions, the amphiphilic polymer forms core-shell-corona micelles with free thiols in the shell. Cross-linking of the micelles within the shell reduces their critical micellization concentration and enhances their stability against severe conditions. The redox-sensitive cross-linkage allows the facilitated release of entrapped anticancer drugs in the cytoplasm in response to the intracellular reductive environment. With enhanced stability during circulation after administration, and accelerated intracellular drug release at the target site, the biocompatible and biodegradable shell-cross-linked polymeric micelle is promising as a drug vehicle for cancer chemotherapy.

Development of Disulfide Core‐Crosslinked Pluronic Nanoparticles as an Effective Anticancer‐Drug‐Delivery System

“…It is conceivable that paclitaxel-loaded Plu-SH micelles are passively targeted to the tumor tissue through the enhanced permeation and retention (EPR) effect. [39] The results show the quick release of paclitaxel from the Plu-SH micelles in an excess of DTT, similar to the GSH concentration present in cancer cells and the stability at plasma GSH levels. [40] This study demonstrates that Plu-SH nanoparticles, as carriers for paclitaxel, can be developed for efficient delivery into cancer cells.…”

Polymeric micelles: authoritative aspects for drug delivery

“…The shell cross-linked micelles lead to formation of stable nanosized hollow particles by removal of the cores after cross-linking and then hydrophilic drugs can be encapsulated inside [216,217]. Hence, reversibly shell cross-linked micelles based on triblock copolymer composed of poly(aliphatic ester), polyphosphoester, and PEG demonstrating improved physical stability were reported [218].…”

“…Thus, polymers containing disulfide bonds can be considered as thiol-as well as redox-responsive. Wang et al recently reported synthesis of reversibly cross-linked triblock copolymer PCL-b-poly(2,4-dinitrophenylthioethyl ethylene phosphate)-b-PEG [218]. After deprotection, core-shell-corona micelles were formed in aqueous milieu from the resultant triblock copolymer bearing thiol groups.…”

Reduction-Responsive Polymeric Micelles and Vesicles for Triggered Intracellular Drug Release

“…Xu et al found that SCL micelles based on PEG-b-PCL diblock copolymer with two lipoyl groups at its junction (PEG-L 2 -PCL) showed markedly enhanced stability against dilution, whereas released DOX rapidly in response to 10 mM DTT with about 75% release in 9 h under otherwise the same conditions (87). Wang et al prepared reduction-sensitive SCL micelles from pendant thiol-containing PEG-bpoly(thioethyl ethylene phosphate)-b-PCL (PEG-b-PEEP SH -b-PCL) triblock copolymer followed by oxidative cross-linking in the H 2 O 2 aqueous solution (76). Thus formed SCL micelles revealed enhanced stability against FIG.…”