Optimization of amino acid-based poly(ester urea urethane) nanoparticles for the systemic delivery of gambogic acid for treating triple negative breast cancer

Amino acid-based poly(ester urea urethane) (AA-PEUU) is developed from amino acid-based ester urea building blocks interconnected with urethane blocks functionalized with poly(ethylene glycol) (PEG). Each functional block consists of structural design features that could impact the properties and performances of AA-PEUU as a nanocarrier for the systemic delivery of gambogic acid (GA). The multifunctional AA-PEUU structure provides broad tunability to enable the optimization of nanocarriers. The study investigates the structure–property relationship by fine-tuning the structure of AA-PEUU, including the amino acid type, hydrocarbons, the ratio of functional building blocks, and PEGylation, to identify the nanoparticle candidate with optimized delivery performances. Compared to free GA, the optimized PEUU nanocarrier improves the intratumoral distribution of GA by more than 9-fold, which significantly enhances the bioavailability and persistence of GA after intravenous administration. In an MDA-MB-231 xenograft mouse model, GA delivered by the optimized AA-PEUU nanocarrier exhibits significant tumor inhibition, apoptosis induction, and the anti-angiogenesis effect. The study demonstrates the potency of engineering AA-PEUU nanocarriers with tailor-designed structures and versatile tunability for the systemic delivery of therapeutics in the treatment of triple negative breast tumor.