Axitinib-Loaded PEGylated Nanocrystal with Enhanced In Vivo Pharmacokinetics and Biodistribution for Triple-Negative Breast Cancer Treatment

Triple negative breast cancer (TNBC) represents an intensely malignant variant of breast cancer with restricted therapeutic approaches and poor patient prognosis. Angiogenesis driven by vascular endothelial growth factor receptor (VEGFR) is a critical pathway in TNBC progression. Axitinib, a potent VEGFR tyrosine kinase inhibitor approved for renal cell carcinoma, holds promise for repurposing in TNBC therapy. However, its clinical translation is hindered by poor aqueous solubility, low oral bioavailability, short plasma half-life, and dose-limiting toxicities. This study aimed to develop an optimized Axitinib nanocrystal formulation stabilized with Soluplus and coated with DSPE-mPEG 2000 to overcome these biopharmaceutical limitations. The F2-nanocrystal exhibited favorable physicochemical properties, including particle size of (73.77 ± 0.429 nm), polydispersity index (PDI), (0.070 ± 0.002), zeta potential (−7.8 ± 1 mV), and high drug content (99.89 ± 1.2%) with enhanced stability at 2–8 °C. In vitro studies demonstrated a sustained and pH-responsive drug release, improved cytotoxicity (1.79-fold at 24 h and 2.29-fold at 48 h), enhanced cellular uptake, ROS formation, and apoptotic potential in MDA-MB-231 cells compared to plain Axitinib. Pharmacokinetic studies revealed a significant improvement in systemic exposure, bioavailability, and circulation time of the F2-Nanocrystal following both oral and intravenous administration, accompanied by altered biodistribution favoring sustained organ retention with reduced off-target accumulation. Collectively, this dual delivery (oral and intravenous) approach showcases the potential of Axitinib-nanocrystal as a multifaceted system to enhance therapeutic efficacy and reposition Axitinib as an effective antiangiogenic therapy for TNBC.