A\nGeneral “Two-Lock” Strategy to Enhance\nDrug Loading and Lysosomal Escape in Intelligent Boronate Ester Polymer\nNanoparticles for Improved Chemotherapy

Boronate\nester can be used to prepare intelligent polymer nanoparticles\n(NPs). However, the traditional boronate ester polymer NPs made of\nboronic acid and diols using a “single-lock” strategy\n(B–O NPs) exhibit low drug loading capacity (DLC) and insufficient\nlysosomal escape ability, resulting in limited antitumor efficacy.\nWe develop a “two-lock” strategy that combines dodecanamine\nand boronic acid using boron–nitrogen (B ← N) coordination\nto enhance the formation of a boronate ester polymer. Through this\nstrategy, amphiphilic dextran and poly(vinyl alcohol) are synthesized\nthrough conjugation with the phenylboronic acid (PBA)/dodecanamine\ncomplex. The amphiphilic dextran encapsulates paclitaxel (PTX) to\nform B–N–O NPs with a higher DLC than their “single-lock”\ncompartments due to enhanced boronate ester stability and improved\nhydrophobic drug-polymer interactions. Moreover, the B–N–O\nNPs release more PTX under acidic conditions compared with the B–O\nNPs. To demonstrate the generality of this “two-lock”\nstrategy, eight polymer prodrug B–N–O NPs employing\npoly(vinyl alcohol) or dextran, along with PBA-modified gemcitabine,\nfluorouracil, and 7-ethyl-10-hydroxycamptothecin, or boronic acid-containing\nbortezomib and dodecanamine, are prepared, showing overall enhanced\nDLC and higher responsive drug release efficiency compared to B–O\nNPs. Importantly, B–N–O NPs with a combination of dodecanamine\nand boronic acid show a better lysosomal escape capability than B–O\nNPs. Moreover, B–N–O NPs exhibit stronger cytotoxicity\ncompared to B–O NPs and free drugs in vitro. Their enhanced\ndrug loading, responsive drug release, and lysosomal escape abilities\ncontribute to enhanced antitumor efficacy in vivo. This “two-lock”\nstrategy can be a general and convenient method to prepare responsive\npolymer NPs with enhanced anticancer efficacy.