Enhanced drug resistance suppression by serum-stable micelles from multi-arm amphiphilic block copolymers and tocopheryl polyethylene glycol 1000 succinate

Aim: To develop a robust drug-delivery system using multi-arm amphiphilic block copolymers for enhanced efficacy in cancer therapy.
Materials & methods: Two series of amphiphilic polymer micelles, PEG-b-PCLm and PEG-b-PCLm/TPGS, were synthesized. Doxorubicin (DOX) loading into the micelles was achieved via solvent dialysis.
Results: 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-PEG47-b-PCL21/TPGS micelles effectively suppressed drug-resistant MCF-7/ADR cells.
Conclusion: 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 in vivo.
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-PEG47 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 NPEG/NPCL 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).
In vitro 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.
In vivo distribution and antitumor profiles: evaluated in vivo tumor accumulation of micelles using BALB/c nude mice, demonstrating higher FITC accumulation in tumors. Conducted in vivo 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.