CD44 Receptor-Mediated Delivery of ROS/pH Dual-Sensitive Nanoparticles Based on Poly(Ethylene...

This study aimed to develop and evaluate acidic pH- and reactive oxygen species (ROS)-sensitive triblock copolymer nanoparticles, composed of poly(ethylene glycol) (PEG), poly(doxorubicin) (DOX), and hyaluronic acid (HA), for targeted anticancer drug delivery.

PEG-PolyDOX (PPD) diblock copolymer and PEG-PolyDOX-HA (PPDHA) triblock copolymer nanoparticles were synthesized and characterized for their responsiveness to tumor microenvironmental conditions, including acidic pH and oxidative stress. In vitro assays were conducted using MDA-MB-231 breast cancer cells to assess cytotoxicity, apoptosis, necrosis, and CD44 receptor-mediated uptake. In vivo biodistribution and therapeutic efficacy were evaluated in an MDA-MB-231 xenograft mouse model compared with DOX and PPD nanoparticles.

PPDHA nanoparticles exhibited morphological and size distribution changes, along with accelerated DOX release, under acidic pH and H₂O₂ conditions. They effectively induced apoptosis and necrosis in breast cancer cells and showed dose-dependent cytotoxicity. CD44 receptor-mediated uptake enabled preferential delivery of PPDHA nanoparticles to MDA-MB-231 cells. In vivo, PPDHA nanoparticles accumulated more efficiently in MDA-MB-231 tumors than in NIH3T3 tumors and significantly suppressed tumor growth compared with DOX or PPD nanoparticles.

PPDHA nanoparticles demonstrated tumor-specific delivery and superior anticancer efficacy in vitro and in vivo. These findings suggest that PPDHA nanoparticles are promising candidates for targeted anticancer drug delivery.