Combination Therapeutic Effect of Psoralen and Paclitaxel-Loaded Superparamagnetic Iron Oxide Nanoparticles for the Treatment of Triple-Negative Breast Cancer

Manling Du,1– 5,&ast; Fengjie Liu,1– 4,6,&ast; Panpan Wang,7,&ast; Mulazim Hussain Asim,8 Qian Liu,1– 5 Qianwen Li,1– 5 Mengjie Xie,1– 5 Kewei Zhang,1– 5 Zhenjiang Yang,9 Yu Cai1– 51State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, People’s Republic of China; 2International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China, Jinan University, Guangzhou, People’s Republic of China; 3Guangdong Key Laboratory of Traditional Chinese Medicine Informatization, Jinan University, Guangzhou, People’s Republic of China; 4International Science and Technology Cooperation Base of Guangdong Province, Jinan University, Guangzhou, People’s Republic of China; 5School of Pharmacy, Jinan University, Guangzhou, People’s Republic of China; 6School of Traditional Chinese Medicine, Jinan University, Guangzhou, People’s Republic of China; 7Department of Chinese Medicine, The First Affiliated Hospital of Jinan University, Guangzhou, People’s Republic of China; 8College of Pharmacy, University of Sargodha, Sargodha, Pakistan; 9Department of Oncology and Hematology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenjiang Yang; Yu Cai, Email dzjysz@163.com; caiyu8@sohu.comPurpose: To overcome dose-limiting toxicity and paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) therapy, as well as the asynchronous in vivo biodistribution of PTX and psoralen (PSO) combination regimens, we developed a highly biocompatible, magnetically targeted nano-co-delivery system.Methods: Paclitaxel/psoralen-loaded magnetic composite nanoparticles (P/P-TCNs) were fabricated via nanoprecipitation. The nanocarriers comprise a poly(lactic-co-glycolic acid) (PLGA) core co-encapsulating both therapeutic agents and superparamagnetic iron oxide nanoparticles (SPIONs), shielded by a stabilizing outer phospholipid layer.Results: Physiochemically, P/P-TCNs exhibited uniform nanoscale dimensions, a negative surface charge, robust superparamagnetism, and synchronized drug release profiles. In vitro, P/P-TCNs significantly enhanced intracellular drug accumulation in 4T1 murine breast cancer cells, inducing profound G2/M cell cycle arrest and augmented apoptotic response. In vivo live imaging of tumor-bearing mice revealed that under an external magnetic field, P/P-TCNs selectively and efficiently accumulated at the tumor site via tail vein injection. This magnetically guided co-delivery achieved a potent tumor inhibition rate of > 85%, significantly outperforming both the free drug combination and non-targeted nanoparticle controls. Furthermore, the nanoplatform demonstrated excellent hemocompatibility (< 5% hemolysis) and negligible systemic toxicity in major organs.Conclusion: P/P-TCNs facilitate the synchronized, safe, and highly efficient co-delivery of PTX and PSO. By maximizing nanocarrier‑facilitated combinatorial anti-TNBC efficacy while minimizing off-target toxicity, this biocompatible magnetic nanoplatform represents a promising translational strategy for the clinical management of refractory TNBC.Keywords: superparamagnetic iron oxide nanoparticles, paclitaxel, psoralen, triple-negative breast cancer