Synthesis and properties of a dually cleavable graft copolymer comprising pendant acetal linkages

Abstract

A novel disulfide-and acetal-linked graft copolymer (SACG) comprising acetal-bridged poly-(3-caprolactone)-b-poly(ethylene glycol) and PEG pendent chains and relatively short polymethacrylate backbone (DP z 24) was synthesized and self-assembled for in vitro encapsulation and release of an anticancer drug, doxorubicin (DOX). Three-step reactions involving (i) RAFT copolymerization of 2hydroxyethyl methacrylate and poly(ethylene glycol) methyl ether methacrylate, (ii) ring-opening polymerization to generate PCL chains, and (iii) hydroxyl-vinyloxy adductive reaction to introduce acidcleavable PEG segments were used to achieve the target copolymer. Meanwhile, well-defined normal (CP) and disulfide-linked (SCP) poly(PEG-co-PCL) comb-like copolymers and acid-cleavable poly(PEGco-PCL)-graft-MVPEG copolymer (ACG) were synthesized and acted as analogues of SACG upon external stimuli. The macromolecular architecture significantly affected the melting and crystallization behaviors and aggregation properties of copolymers, and the difference in topology and location of cleavable linkages resulted in distinctly different stimuli-triggered drug release behaviors. Owing to the dissociation and reaggregation of cleaved copolymer aggregates, stimuli-cleavable aggregates in response to external stimuli (pH 5.0, 10 mM DTT) could exhibit faster release kinetics than CP aggregates, and the maximum increment of cumulative release from various aggregates for 72 h was liable to decrease in the order SACG > ACG > SCP > CP. The cumulative release from SACG aggregates could be adjusted in the widest range via addition of different stimuli, revealing the great potential of dually cleavable copolymer aggregates in smart drug delivery systems.

Synthesis and properties of heterografted toothbrush-like copolymers with alternating PEG and PCL grafts and tunable RAFT-generated segments

“…For the T1 copolymer with different weight contents of PEG and PCL segments (f w,PEG ¼ 0.247, f w,PCL ¼ 0.545), one glass transition (T g,PCL ¼ À59.6 C) and two melting peaks (T m,PEG ¼ 24.0 C, T m,PCL ¼ 41.1 C) were observed, and the X c values (X c,PEG ¼ 37.7%, X c,PCL ¼ 22.2%) were smaller than those of the corresponding macromonomers. The result was roughly comparable to that observed in a densely graed copolymer with a polymethacrylate backbone and random PEG and PCL-b-PEG gras, 64 in which the crystallizability of the inner PCL blocks (X c,PCL ¼ 24.3%, f w,PCL ¼ 0.647) was signicantly hindered by the presence of PEG segments in the outlayer. The reduced crystallizability in the toothbrush-like copolymer could be ascribed to the increased crystalline imperfection of short pendent chains (DP PEG z 16, DP PCL z 15), in which the alternating sequences of PEG and PCL gras in the T1 copolymer could further hinder polymer chains from folding and rearranging, resulting in the enhanced structural connement of polymer segments during crystallization than other random gra copolymers.…”

pH-Responsive, Functionalizable Spyrocyclic Polycarbonate: A Versatile Platform for Biocompatible Nanoparticles

“…Further innovative approaches have included multiresponsive polymers that lead to micelle disassembly to trigger release in cells. 14,37,[45][46][47][48] In many micellar systems, the preference for the encapsulation of the cargo over covalent conjugation, difficult self-assembly approaches, and sometimes limited control over loading and product yields make these strategies less attractive for translation. In order to overcome these limitations, we herein report the synthesis of a novel pH responsive, biodegradable polycarbonate, synthesized via an easily accessible ring opening polymerization method.…”

Boronic Acid Shell-Crosslinked Dextran-b-PLA Micelles for Acid-Responsive Drug Delivery

“…Compared with the conventional specific tumor cell surface targeting approach, this pH‐targeting approach is considered to be a more general strategy because of the acidic tumor microclimate in solid tumors. Hence, many acid‐labile chemical bonds, such as maleic acid amide, acetal, hydrazone, and orthoester, have been extensively employed to design acid‐responsive drug delivery systems.…”