Abstract: | In this study, we reported pH-responsive microparticles consisting of poly(D,L-lactide-co-glycolide) (PLGA), aminated hyaluronic acid (aHA) conjugated with 2,3-dimethylmaleic anhydride (DMA, as a pH-responsive cleavable molecule) (aHA-DMA), and doxorubicin (DOX, as an antitumor drug) for local tumor treatment. The DOX-loaded microparticles, denoted as PLGA(aHA-DMA)/DOX MPs, were fabricated using the W1/O/W2 multi-emulsification method. These PLGA(aHA-DMA)/DOX MPs (~10 μm in diameter) accelerated the rate of DOX release at pH 6.8 due to the acidic pH-responsive cleavage of the DMA moieties followed by electrostatic-repulsion between aHA and DOX. This event caused the structural destabilization and collapse of the MPs, leading to the rapid release of DOX. Consequently, the PLGA(aHA-DMA)/DOX MPs resulted in significant inhibition of tumor growth, demonstrating their ability for acidic tumor-specific treatment. |