Unimolecular Micelle for MLN8237 Delivery to Target AURKA-RalA Crosstalk for Ras-Driven Tumor Suppression in Mice Xenografts

Abstract

Targeting Aurora Kinase A (AURKA) to modulate RalA activation offers a promising strategy for tumor suppression in Ras-independent and Ras-dependent cancers. However, clinical use of the AURKA inhibitor MLN8237 (Alisertib) is limited by its hydrophobicity and poor water solubility. To overcome these limitations, here, we developed an enzyme-biodegradable unimolecular micelle (UMM) nanoparticle to deliver MLN8237 (NPMLN) and evaluated its therapeutic efficacy in tumor xenograft models. NPMLN selectively inhibited AURKA, downregulated pSer194 RalA, and suppressed anchorage-independent growth in SKOV3 (Ras-independent) and MIA PaCa-2 (Ras-dependent) cancer cells. Nanoparticles loaded with sulforhodamine B (NPSRB) and IR780 (NPIR780) confirmed enhanced cellular uptake and tumor localization, respectively. Improved solubility and bioavailability enabled low-dose parenteral delivery of MLN8237, achieving significant tumor regression compared to free drug. This correlated with inhibition of AURKA and RalA phosphorylation (pSer194RalA) in both tumors. Together, they highlight the therapeutic potential of NPMLN in targeting AURKA-RalA crosstalk in tumor xenografts.