Polyanhydride\nCopolymer-Based Niclosamide Nanoparticles\nfor Inhibiting Triple-Negative Breast Cancer: Metabolic Responses\nand Synergism with Paclitaxel

The\nheterogeneity of tumors and the lack of effective therapies have resulted in triple-negative\nbreast cancer (TNBC) exhibiting the least favorable outcomes among\nbreast cancer subtypes. TNBC is characterized by its aggressive nature,\noften leading to high rates of relapse, metastasis, and mortality.\nNiclosamide (Nic), an Food and Drug Administration-approved anthelmintic\ndrug, has been repurposed for cancer treatment; however, its application\nfor TNBC is hindered by significant challenges, including strong hydrophobicity,\npoor aqueous solubility, and low bioavailability. This study aimed\nto develop Nic nanoparticles (Nic NPs) using biodegradable and biocompatible\npolyanhydride copolymers to enhance Nic’s bioavailability and\ntherapeutic efficacy. Nic NPs effectively inhibited migration, proliferation,\nand clonogenicity in both murine and human TNBC cells, inducing apoptosis\nand suppressing STAT3 signaling. For the first time, we utilized Raman\nspectroscopy and Seahorse extracellular flux assays to demonstrate\nthe metabolic responses of TNBC cells to Nic NPs, revealing significant\nmetabolic alterations, including the inhibition of mitochondrial respiration\nand glycolysis. Additionally, this study is the first to explore the\ncombination therapy of repurposed Nic with the approved chemotherapeutic\nagent paclitaxel in the 4T1 TNBC immunocompetent mouse model. The\ncombination of Nic NPs and paclitaxel significantly reduced tumor\ngrowth without adversely affecting the body weight of tumor-bearing\nmice. In summary, these findings suggest that Nic NPs could serve\nas a promising component in combination therapies for the effective\ntreatment of TNBC.