Mesoporous Silica Nanoparticle-Based Combination of Niclosamide and Doxorubicin: Effect of Treatment Regimens on Breast Cancer Subtypes.

Overexpressed Wnt/β-catenin signaling acts as a major cancer driver and plays an important role in the development of resistance against cancer chemotherapy. Therefore, the combinatorial approach of downregulating Wnt/β-catenin signaling along with using a chemotherapeutic agent may improve cancer therapy. However, systemic administration of free anticancer agents is nonspecific and poses serious side effects. Hence, the present study aimed at developing mesoporous silica nanoparticle (MSN)-based targeted combination therapy of a Wnt signaling inhibitor, niclosamide (Nic), and a conventional anticancer agent, doxorubicin (Dox). The results demonstrated the reproducible synthesis of highly stable and monodispersed sub-100 nm spherical shaped NPs. In vitro cytotoxicity studies demonstrated that the individual drug formulations caused concentration-dependent cytotoxicity to all of the three breast cancer subtypes, with higher concentrations being more cytotoxic. Further, sequential and concurrent combination of Nic-loaded MSNs with Dox-loaded MSNs was synergistic and caused significantly enhanced death in all breast cancer subtypes. Quantification of the combinatorial efficacy suggested that multiple combinatorial pairs were synergistic in all of the breast cancer types for both (sequential and concurrent) treatment regimens. However, the extent of synergism varied between the two treatment regimens in different clinical subtypes of breast cancer. Overall, the combination of Nic-loaded MSNs with Dox-loaded MSNs holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of the clinical subtype in both sequential and concurrent treatment regimens.