Combination of mannoside and phenylboronic acid polycaprolactone polymers for doxorubicin-encapsulated polymersome nanomedicine targeting MDA-MB-231 cancer cells.

Abstract

This study aims to create glyco-based nanoparticles (NPs) with high drug-loading capability for targeted cancer treatment, specifically against MDA-MB-231 breast cancer cells. Traditional NPs have faced limitations due to low drug-loading capacities, leading to suboptimal therapeutic effectiveness and significant side effects. To overcome these limitations, DOX@pB-pM NP were synthesized using a self-assembly combination method of two poly(ε-caprolactone) (PCL) based polymers, mannoside-b-PCL (pM) and phenylboronic acid (PBA)-mPEG-t-PCL (pB). The pM polymer synthesis includes a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc) reaction. DOX@pB-pM NP's mannose moiety is specifically engineered to target MDA-MB-231 cells, while the core of the NPs is made of hydrophobic, biodegradable polyester PCL. The functions of mPEG and PBA in the pB tri-block copolymer are to enhance biocompatibility and drug-loading efficiency, respectively. Additionally, mPEG can reduce nonspecific interactions. The PBA on the pB introduces a hydrophobic segment to the copolymer, which can improve the interaction with water-insoluble drugs, doxorubicin (DOX). The PBA moiety can also provide additional functionality, such as pH-responsive and H₂O₂-responsive drug release, which is particularly useful in targeting the tumor's acidic and oxidative microenvironment. The PBA groups convert them to boronic acid and 4-(hydroxymethyl) phenol, which destroys the NP core and causes DOX release, resulting in cell death. The in vitro release profile of DOX from the DOX@pB-pM NPs was evaluated under various conditions, including different pH levels and the presence or absence of H₂O₂, to simulate the acidic tumor microenvironment. The cytotoxicity of the DOX@pB-pM NPs was assessed using the MTT assay, which demonstrated significant inhibition of MDA-MB-231 breast cancer cell growth by DOX@pB-pM NPs. By combining mannose for the targeting of MDA-MB-231 breast cancer cells and fine-tuning the ratio of pM and pB polymers, the NPs showed good therapeutic efficacy. Importantly, pB-pM NPs displayed good biocompatibility, with no significant effect on cell survival even at high concentrations, indicating their potential as safe drug carriers. These data show that DOX@pB-pM NPs can potentially improve cancer therapeutic efficacy and safety.