Harnessing nanoencapsulation for the repurposing of hydroquinidine against breast cancer

Repurposing drugs beyond their original medical indications can facilitate cost- and time-effective drug development and a sustainable drug development process. Nanoencapsulation strategies can further expand the number of potentially suitable drug candidates for repurposing. In this study, we explored the anticancer efficacy of hydroquinidine (a class IA antiarrhythmic cinchona alkaloid drug) loaded into PLGA nanoparticles (HQ-NP) on breast cancer cells. The study compared HQ-NP to soluble hydroquinidine (HQ sol ) in estrogen receptor-positive MCF7 and triple-negative MDA-MB-231 breast cancer cell lines. Overall, nanoencapsulation resulted in more potent and selective toxicity in comparison to soluble drug. The mechanisms involved inducing apoptosis and oxidative stress, disruption of mitochondrial membrane potential, and suppression of cell proliferation. The enhanced potency of HQ-NP was consistent across multiple assays and on both cell lines, suggesting a broad applicability in different breast cancer subtypes. In silico analyses indicated the cancer-related pathways, such as PI3K-Akt and cAMP signaling, as potential targets of HQ, which is likely to be driven by the putative inhibition of voltage-gated ion channels as suggested by molecular docking studies. This research highlights the potential of HQ-NP as a novel, multi-modal anticancer agent for breast cancer treatment, warranting further investigation towards clinical application.