DOI: 10.6084/m9.figshare.26364398
title: Enhanced drug resistance suppression by serum-stable micelles from multi-arm amphiphilic block copolymers and tocopheryl polyethylene glycol 1000 succinate

description: <b>Aim:</b> To develop a robust drug-delivery system using multi-arm amphiphilic block copolymers for enhanced efficacy in cancer therapy. <b>Materials & methods:</b> Two series of amphiphilic polymer micelles, PEG-b-PCL<sub>m</sub> and PEG-b-PCL<sub>m</sub>/TPGS, were synthesized. Doxorubicin (DOX) loading into the micelles was achieved via solvent dialysis. <b>Results:</b> The micelles displayed excellent biocompatibility, narrow size distribution, and uniform morphology. DOX-loaded micelles exhibited enhanced antitumor efficacy and increased drug accumulation at tumor sites compared with free DOX. Additionally, 4A-PEG<sub>47</sub>-b-PCL<sub>21</sub>/TPGS micelles effectively suppressed drug-resistant MCF-7/ADR cells. <b>Conclusion:</b> This study introduces a novel micelle formulation with exceptional serum stability and efficacy against drug resistance, promising for cancer therapy. It highlights innovative strategies for refining clinical translation and ensuring sustained efficacy and safety <i>in vivo</i>. Multi-arm amphiphilic block copolymer synthesis: prepared various multi-arm amphiphilic block star copolymers with different numbers of arms and molecular weights. Coupled with carboxyl-terminated monomethoxy poly(ethylene glycol) to form PCL-b-PEG<sub>47</sub> block copolymers. Micelle formation and size: assembled micelles from multi-arm block copolymers (2A-25/47, 4A-m/47, and 6A-21/47) through dialysis. Controlled particle size (50–500 nm) based on PCL length and arm number, influencing drug release and loading. Drug-loading capacity (DLC): Investigated DLC of DOX-loaded micelles, showing higher values for four-arm copolymers with higher N<sub>PEG</sub>/N<sub>PCL</sub> ratio. Four-arm copolymer micelles demonstrated higher DLC than two-arm or six-arm counterparts. Micelle stability: determined critical micelle concentration (CMC) values, indicating low concentrations for enhanced stability. Evaluated serum protein stability using dynamic laser light scattering (DLLS), demonstrating distinct particle sizes. Biocompatibility assessment: confirmed good biocompatibility of synthesized block copolymers through cell toxicity experiments on breast cancer cells (MCF-7). <i>In vitro</i> antitumor assay: demonstrated effective antitumor activity against both MCF-7 and MCF-7/ADR cells using DOX-loaded TPGS mixed micelles. Revealed the reversal of drug resistance in tumor cells, enhancing therapeutic efficacy. Cellular uptake of DOX: investigated cellular uptake of DOX, showing improved endocytosis in doxorubicin-resistant breast cancer cells with TPGS-containing micelles. Drug resistance suppression mechanism: explored the mechanism of drug-resistance suppression, highlighting enhanced apoptosis and decreased P-glycoprotein expression with TPGS. <i>In vivo</i> distribution and antitumor profiles: evaluated <i>in vivo</i> tumor accumulation of micelles using BALB/c nude mice, demonstrating higher FITC accumulation in tumors. Conducted <i>in vivo</i> antitumor assay, indicating remarkable efficacy in chemotherapy for drug-resistant tumors. Therapeutic potential: established the therapeutic potential of DOX-micelle-TPGS, significantly impeding further tumor growth and maintaining tumor volume within a specific range.