| Summary: | Introduction: Owing to its high prevalence, colossal potential of chemoresistance, metastasis, and relapse, breast cancer (BC) is the second leading cause of cancer-related fatalities in women. Several treatments (eg, chemotherapy, surgery, radiations, hormonal therapy, etc.) are conventionally prescribed for the treatment of BC; however, these are associated with serious systemic aftermaths. In this research, we aimed to design a multiprong targeting strategy for concurrent action against different phenotypes of BC (MCF-7 and SK-BR-3) and tumor-associated macrophages (TAMs) for relapse-free treatment of BC. Methods: Paclitaxel (PTX) and tamoxifen (TMX) co-loaded chitosan (CS) nanoparticles (NPs) were prepared using the ionic-gelation method and optimized using the Design Expert (R) software by controlling different material attributes. For selective targeting through CD44-receptors that are heavily expressed on the BC cells and TAMs, the fabricated NPs (PTX-TMX-CS-NPs) were functionalized with hyaluronic acid (HA) as a targeting ligand. Results: The optimized HA-PTX-TMX-CS-NPs exhibited desired physicochemical properties (PS similar to 230 nm, PDI 0.30, zeta potential similar to 21.5 mV), smooth spherical morphology, high encapsulation efficiency (PTX similar to 72% and TMX similar to 97%), good colloidal stability, and biphasic release kinetics. Moreover, the lowest cell viability depicted in MCF-7 (similar to 25%), SK-BR-3 (similar to 20%), and RAW 264.7 cells (similar to 20%), induction of apoptosis, cell cycle arrest, enhanced cell internalization, and alleviation of MCF-7 and SK-BR-3 migration proved the superior anticancer potential of HA-PTX-TMX-CS-NPs compared to unfunctionalized NPs and other control medicines. Conclusion: HA-functionalization of NPs is a promising multiprong strategy for CD44-receptors-mediated targeting of BC cells and TAMs to mitigate the progression, metastasis, and relapse in the BC.
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