Boronate ester can be used to prepare intelligent polymer nanoparticles (NPs). However, the traditional boronate ester polymer NPs made of boronic acid and diols using a "single-lock" strategy (B-O NPs) exhibit low drug loading capacity (DLC) and insufficient lysosomal escape ability, resulting in limited antitumor efficacy. We develop a "two-lock" strategy that combines dodecanamine and boronic acid using boron-nitrogen (B ← N) coordination to enhance the formation of a boronate ester polymer. Through this strategy, amphiphilic dextran and poly(vinyl alcohol) are synthesized through conjugation with the phenylboronic acid (PBA)/dodecanamine complex. The amphiphilic dextran encapsulates paclitaxel (PTX) to form B-N-O NPs with a higher DLC than their "single-lock" compartments due to enhanced boronate ester stability and improved hydrophobic drug-polymer interactions. Moreover, the B-N-O NPs release more PTX under acidic conditions compared with the B-O NPs. To demonstrate the generality of this "two-lock" strategy, eight polymer prodrug B-N-O NPs employing poly(vinyl alcohol) or dextran, along with PBA-modified gemcitabine, fluorouracil, and 7-ethyl-10-hydroxycamptothecin, or boronic acid-containing bortezomib and dodecanamine, are prepared, showing overall enhanced DLC and higher responsive drug release efficiency compared to B-O NPs. Importantly, B-N-O NPs with a combination of dodecanamine and boronic acid show a better lysosomal escape capability than B-O NPs. Moreover, B-N-O NPs exhibit stronger cytotoxicity compared to B-O NPs and free drugs in vitro. Their enhanced drug loading, responsive drug release, and lysosomal escape abilities contribute to enhanced antitumor efficacy in vivo. This "two-lock" strategy can be a general and convenient method to prepare responsive polymer NPs with enhanced anticancer efficacy.
Keywords: boronate ester; chemotherapy; drug loading capacity; lysosomal escape; polymer nanoparticles; responsive release.