pH and thermal dual sensitive injectable microgels loaded with doxorubicin for the localized neoadjuvant chemotherapy of breast cancer

Localized neoadjuvant chemotherapy (NACT) is a widely utilized strategy for breast cancer treatment, aimed at reducing tumor size before surgery and improving rates of pathological complete response (pCR), a critical indicator of favorable long-term outcomes. However, the therapeutic efficacy of NACT is often limited by conventional drug delivery systems, which fail to achieve sufficient drug concentrations within the crucial early treatment window due to slow and nonspecific drug release. To address this challenge, we have fabricated an injectable, pH and thermal dual sensitive microgel by the copolymerization of N-isopropylacrylamide (NIPAM), N-isopropylmethacrylamide (NIPMAM), and methacrylic acid (MAA). These microgels are specifically designed to respond to the acidic and hyperthermic conditions of the breast tumor microenvironment (TME), enabling a tumor-specific burst release of encapsulated drug doxorubicin (DOX). Under simulated TME conditions (pH 5.0, 42°C), the microgels achieve a significant initial burst release of 58.99 % DOX within 4 h, compared to only 21.00 % under physiological conditions (pH 7.4, 37°C). In vitro studies further demonstrate that DOX-loaded microgels could reduce the viability of MCF-7 breast cancer cells to 39.36 % after 48 h at a DOX-equivalent concentration of 4.0 µg/mL. Furthermore, the microgels could effectively mitigate the cytotoxic effects of high concentration DOX on normal cells, preserving greater cell viability compared to free DOX. These findings highlight the potential of this dualsensitive microgel system as an innovative platform for localized NACT, offering enhanced therapeutic efficacy, improved pCR rates, and reduced systemic toxicity.