Stimulus-responsive doxorubicin-conjugated hyaluronic acid/polypyrrole nanoplatform for targeted photothermal chemotherapy of breast cancer

Combination of different therapy modalities has emerged as a promising strategy for effective cancer treatment. Herein, we developed a multifunctional doxorubicin (DOX)-conjugated hyaluronic acid/polypyrrole (HA/PPy) nanoplatform, termed PPy-HA_DOX-CH_t nanoparticles, for the targeted photothermal chemotherapy of breast cancer. This nanoplatform was fabricated through layer-by-layer assembly of dopamine/hydrazide-modified hyaluronic acid (DHHA), hydroxyethyl chitosan, and anti-HER2 antibody-conjugated hyaluronic acid aldehyde on PPy nanoparticles. DHHA was synthesized by successively grafting dopamine and 3,3′-thiodipropionodihydrazide onto the carboxyl groups of HA via carbodiimide reaction for subsequent DOX conjugation through acid-labile hydrazone linkages. We systematically investigated the preparation, physicochemical properties, and anticancer efficacy of the nanoplatform. The results show that the size of PPy nanoparticles synthesized via Fe³⁺-initiated oxidation polymerization is controllable. The nanoplatform exhibits pH/glutathione dual-responsive drug release feature, excellent photothermal performance, enhanced structural stability, and outstanding biocompatibility. In vitro studies reveal that the nanoplatform can be efficiently taken up by MCF-7 cells via HER2-mediated endocytosis and kill them via apoptosis through the combination of PPy-mediated near infrared photothermal therapy and DOX-based chemotherapy. In vivo evaluation demonstrates significant tumor growth suppression. In a word, the as-prepared multifunctional nanoplatform holds substantial potential for targeted combination therapy of breast cancer.