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Photo cleavable thioacetal block copolymers for controlled release.

ABSTRACT: We present a new light cleavable polymer containing o-nitrobenzene thioacetal groups in the main chain. By conjugation to a PEG block, we synthesized block copolymers capable of forming nanoparticles in aqueous solution. We studied drug encapsulation and release using the model drug Nile Red. Irradiation with UV-A light (365 nm) leads to efficient degradation of the polymers and associated burst release of the payload. Unlike other thioacetal and thioketal polymers, these polymers are stable to reactive oxygen species (ROS), preventing non-triggered release. Moreover, the nanocarriers showed low cytotoxicity in cell viability experiments.

SUBMITTER: Men Y

PROVIDER: S-EPMC8240465 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Photo cleavable thioacetal block copolymers for controlled release.

Men Yongjun Y Brevé Tobias G TG Liu Huanhuan H Denkova Antonia G AG Eelkema Rienk R

Polymer chemistry 20210608 25

We present a new light cleavable polymer containing <i>o</i>-nitrobenzene thioacetal groups in the main chain. By conjugation to a PEG block, we synthesized block copolymers capable of forming nanoparticles in aqueous solution. We studied drug encapsulation and release using the model drug Nile Red. Irradiation with UV-A light (365 nm) leads to efficient degradation of the polymers and associated burst release of the payload. Unlike other thioacetal and thioketal polymers, these polymers are sta ...[more]

PMID: 34262625

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Project description:This work continues our efforts to improve the diagnostic and radiotherapeutic effectiveness of nanomedicine platforms by developing approaches to reduce the non-target accumulation of these agents. Herein, we developed multi-block HPMA copolymers with backbones that are susceptible to cleavage by cathepsin S, a protease that is abundantly expressed in tissues of the mononuclear phagocyte system (MPS). Specifically, a bis-thiol terminated HPMA telechelic copolymer containing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Three maleimide modified linkers with different sequences, including cathepsin S degradable oligopeptide, scramble oligopeptide and oligo ethylene glycol, were subsequently synthesized and used for the extension of the HPMA copolymers by thiol-maleimide click chemistry. All multi-block HPMA copolymers could be labeled by (177)Lu with high labeling efficiency and exhibited high serum stability. In vitro cleavage studies demonstrated highly selective and efficient cathepsin S mediated cleavage of the cathepsin S-susceptible multi-block HPMA copolymer. A modified multi-block HPMA copolymer series capable of Förster Resonance Energy Transfer (FRET) was utilized to investigate the rate of cleavage of the multi-block HPMA copolymers in monocyte-derived macrophages. Confocal imaging and flow cytometry studies revealed substantially higher rates of cleavage for the multi-block HPMA copolymers containing the cathepsin S-susceptible linker. The efficacy of the cathepsin S-cleavable multi-block HPMA copolymer was further examined using an in vivo model of pancreatic ductal adenocarcinoma. Based on the biodistribution and SPECT/CT studies, the copolymer extended with the cathepsin S susceptible linker exhibited significantly faster clearance and lower non-target retention without compromising tumor targeting. Overall, these results indicate that exploitation of the cathepsin S activity in MPS tissues can be utilized to substantially lower non-target accumulation, suggesting this is a promising approach for the development of diagnostic and radiotherapeutic nanomedicine platforms.

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Photo cleavable thioacetal block copolymers for controlled release.

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Photo cleavable thioacetal block copolymers for controlled release.

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