Abstract
Triple-Negative Breast Cancer (TNBC) is considered as the most onerous cancer subtype, lacking the estrogen, progesterone, and HER2 receptors. Evaluating new markers is an unmet need for improving targeted therapy against TNBC. TNBC depends on several factors, including hypoxia development, which contributes to therapy resistance, immune evasion, and tumor stroma formation. In this study, we studied the curcumin analogue (3,4-Difluorobenzylidene Curcumin; CDF) encapsulated bovine serum albumin (BSA) nanoparticle for tumor targeting. For tumor targeting, we conjugated Acetazolamide (ATZ) with CDF and encapsulated it in the BSA to form a nanoparticle (namely BSA-CDF-ATZ). The in vitro cytotoxicity study suggested that BSA-CDF-ATZ is more efficient when compared to free CDF. The BSA-CDF-ATZ nanoparticles showed significantly higher cell killing in hypoxic conditions compared to normoxic conditions, suggesting better internalization of the nanoparticles into cancer cells under hypoxia. Fluorescent-dye labeled BSA-CDF-ATZ revealed higher cell uptake of the nanoparticle compared to free dye indicative of better delivery, substantiated by a high rate of apoptosis-mediated cell death compared to free CDF. The significantly higher tumor accumulation and low liver and spleen uptake in TNBC patient-derived tumor xenograft models confirm the significant potential of BSA-CDF-ATZ for targeted TNBC imaging and therapy.
Highlights
Cancer still remains one of the major causes of death in the United States, taking more than half a million lives annually, and with approximately 1.5 million new cases diagnosed each year [1]
Our study described in this paper is lined on the concept of self-assembling bovine serum albumin (BSA) nanoparticle encapsulated with CDF that is functionalized with targeting ligands utilizing strain-promoted copper-free click chemistry [25,26], the 1, 3 dipolar azide-alkyne cycloaddition
The quickly developing malignant cells produce an absence of oxygen, bringing down the pH which will bring about the overexpression of the Carbonic anhydrase IX receptor
Summary
Cancer still remains one of the major causes of death in the United States, taking more than half a million lives annually, and with approximately 1.5 million new cases diagnosed each year [1]. Several therapeutic and diagnostic arsenals have been developed to fight against cancer. The therapeutic success of TNBC is poor [2]. The new therapeutics, including chemotherapy, immunotherapy, and kinase inhibitors, have been developed, but their effect is still merely marginal. The DNA intercalating taxanes, platinum compounds, and tyrosine and serine-threonine kinase inhibitors, such as Everolimus and Cetuximab, are the most common and conventional therapeutic strategies for TNBC. In clinical trials, it may lead to drug resistance in TNBC patients. Evaluating new targeting agents and exploiting them for early diagnosis and tumor-specific therapy is an urgent need. Nanomedicines have proven to be a multitasking drug delivery vehicle for tumor
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