Fabrication of Hyperbranched Block-Statistical Copolymer-Based Prodrug with Dual Sensitivities for Controlled Release

Abstract

Dendrimer with hyperbranched structure and multivalent surface is regarded as one of the most promising candidates close to the ideal drug delivery systems, but the clinical translation and scale-up production of dendrimer has been hampered significantly by the synthetic difficulties. Therefore, there is considerable scope for the development of novel hyperbranched polymer that can not only address the drawbacks of dendrimer but maintain its advantages. The reversible addition-fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) technique has enabled facile preparation of segmented hyperbranched polymer (SHP) by using chain transfer monomer (CTM)-based double-head agent during the past decade. Meanwhile, the design and development of block-statistical copolymers has been proven in our recent studies to be a simple yet effective way to address the extracellular stability vs intracellular high delivery efficacy dilemma. To integrate the advantages of both hyperbranched and block-statistical structures, we herein reported the fabrication of hyperbranched block-statistical copolymer-based prodrug with pH and reduction dual sensitivities using RAFT-SCVP and post-polymerization click coupling. The external homo oligo(ethylene glycol methyl ether methacrylate) (OEGMA) block provides sufficient extracellularly colloidal stability for the nanocarriers by steric hindrance, and the interior OEGMA units incorporated by the statistical copolymerization promote intracellular drug release by facilitating the permeation of GSH and H for the cleavage of the reduction-responsive disulfide bond and pH-liable carbonate link as well as weakening the hydrophobic encapsulation of drug molecules. The delivery efficacy of the target hyperbranched block-statistical copolymer-based prodrug was evaluated in terms of in vitro drug release and cytotoxicity studies, which confirms both acidic pH and reduction-triggered drug release for inhibiting proliferation of HeLa cells. Interestingly, the simultaneous application of both acidic pH and GSH triggers promoted significantly the cleavage and release of CPT compared to the exertion of single trigger. This study thus developed a facile approach toward hyperbranched polymer-based prodrugs with high therapeutic efficacy for anticancer drug delivery.

Branched and Dendritic Polymer Architectures: Functional Nanomaterials for Therapeutic Delivery

“…114 and colleagues, to form highly branched polymer prodrug conjugates with both redox sensitive disulphide groups and acid sensitive groups carbonate groups. 116 The presence of acidic pH conditions or glutathione environments enhances the release of camptothecin, with the polymer system having IC50 values of 365.1 g/ml, to HeLa cell-line with an MTS cell viablilty assay.…”

Long‐Chain Hyperbranched Polymers: Synthesis, Properties, and Applications

“…And the conjugate‐based nanoparticles degraded to low‐molar‐mass products in the presence of enzymes of papain or cathepsin B, and also demonstrated pH‐sensitive drug release . Very recently, a kind of LCHBP‐based prodrug with pH and reduction dual sensitivities was fabricated via RAFT polymerization of glycidyl methacrylate and oligo(ethylene glycol methyl ether methacrylate) in the presence of reducible inimer, and post‐polymerization click coupling to attach the anticancer drug, camptothecin …”

“…Even at this early stage of the development of this class of LCHBPs we are already seeing the emergence of a number of interesting applications being developed, which are largely dependent on their unusual long‐chain topological structures and certain peculiar properties. A variety of guest molecules including metal nanoparticles, drugs, and imaging agents have been transported with LCHBPs focusing on the stabilization of catalysts, and biomedicine as well as diagnostic purposes . The special molecular constructions of LCHBPs also provide them with promising applications in electrical conductivity and chemical sensing …”

Fabrication of Reduction‐Sensitive Amphiphilic Cyclic Brush Copolymer for Controlled Drug Release

“…Polymers with branched topological structures, including dendrimers, star‐shaped polymers, segmented hyperbranched polymers, and cyclic brush polymers, are a promising class of nanocarriers for controlled delivery applications due to the ability to form unimolecular nanoparticles with enhanced stability and structural integrity, which can minimize the off‐target‐associated side effect and promote the long circulation required in vivo. Among these architectures, cyclic brush polymer with uniformly radiating polymer brushes grafting from a cyclic core template is probably considered as the most unique topology, which has attracted increasing attention in recent years due to the simultaneous functionalities of the cyclic core and the polymer brushes.…”