CD44 Receptor-Mediated Delivery of ROS/pH Dual-Sensitive Nanoparticles Based on Poly(Ethylene Glycol)-b-Poly(Doxorubicin)-b-Hyaluronic Acid Copolymer.

PURPOSE: 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.

METHODS

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.

RESULTS

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.

CONCLUSION

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.