A Biomimetic Drug Delivery System Targeting Tumor Hypoxia in Triple-Negative Breast Cancers

Abstract

Triple-negative breast cancer (TNBC) is amongst the most challenging tumor subtypes because it presents itself without the estrogen, progesterone, and HER2 receptors. Hence, assessing new markers is an essential requirement for enhancing its targeted treatment. The survival of TNBC relies upon the advancement of hypoxia that contributes to treatment resistance, immune response resistance, and tumor stroma arrangement. Here, we explored bovine serum albumin (BSA) nanoparticle encapsulating the anti-cancer drug Paclitaxel (PTX) for cell-killing mediated by tumor hypoxia. For targeting hypoxia, we conjugated Acetazolamide (ATZ) with BSA nanoparticle that encapsulated PTX (referred hereon as BSA-PTX-ATZ) utilizing copper-free click chemistry, specifically the Strain-Promoted Alkyne Azide Cycloaddition (SPAAC). The in-vitro cell killing study uncovered that BSA-PTX-ATZ is more productive contrasted with free PTX. The evaluations of the physio-chemical properties of BSA-PTX-ATZ proves that the shelf-life is approximately two months when stored either at room or freezing temperatures or under refrigerated conditions. There is no leakage of PTX from the formulation during that period, while their nanoparticulate nature remained undisturbed. The BSA-PTX-ATZ nanoparticles indicated altogether higher cell killing in hypoxic conditions contrasted with normoxia proposing the hypoxia-mediated delivery mechanism of the activity of the formulation. Higher cell uptake found with fluorescent-marked BSA-PTX-ATZ shows CA-IX mediated cell uptake, substantiated by the prominent apoptotic cell death contrasted with free PTX.