Dual Targeting of Prostate Cancer Cells and Tumor-Associated Macrophages for Mitigating Tumorigenesis and Metastasis: Hyaluronic Acid Functionalized Polymeric Nanospheres for CD44-Mediated Active Targeting

Abstract

AbstractProstate cancer (PC) is the second leading cause of cancer-related fatalities in men due to enormous ability of progression, metastasis, and development of multidrug resistance (MDR). The existing conventional therapies are producing reasonable clinical response in PC patients; however, they are associated with substantial limitations. The advent of nanotechnology has resolved several key issues associated with conventional therapies; however, undesired pharmacokinetics, non-selective targeting, and evasion of tumor-associated macrophages (TAMs) yet persist as paramount challenge to current nano-therapies. Herein, we proposed dual targeting strategy for concurrent action against PC cells and TAMs hosted by tumor microenvironment. Henceforth, chitosan (CS)-based polymeric nanospheres (PNSPs) were fabricatedviaionic-gelation method and functionalized with hyaluronic acid (polyanionic biological macromolecule)viaelectrostatic adsorption. HA was employed as a targeting ligand for CD44 receptors that are overexpressed on PC cells and TAMs. The optimized PNSPs were extensively pondered for physicochemical properties (particle size ⁓160 nm, PDI 0.453, zeta potential ⁓30 mV), morphology (smooth spherical), stability, release kinetics (biphasic and pH-responsive), cytotoxicity (lowest IC50), cell uptake efficiency, mechanism of cell internalization (CD44-mediated endocytosis), and anti-metastatic efficacy. Conclusively, our findings warranted that HA-functionalized PNSPs act as a double edge sword for dual targeting of PC cells and TAMs to mitigate cancer progression and metastasis.