Enhanced Delivery of Aurora Kinase A Inhibitor Alisertib via Tumor-Targeting Immunoliposome Nanocomplex for Improved Treatment of Cancers Including Atypical Teratoid/Rhabdoid Tumor

Sang-Soo Kim,1,2 Manish Moghe,1 Antonina S Rait,1 Joe B Harford,2 Esther H Chang1 1Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA; 2SynerGene Therapeutics, Inc., Potomac, MD, USACorrespondence: Esther H Chang, Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA, Email [email protected]: This study explores a nanoparticle-based delivery system for alisertib, a selective aurora kinase A (AURKA) inhibitor. This nanocomplex is designed to enhance tumor-specific delivery. AURKA is overexpressed in various cancers, including atypical teratoid/rhabdoid tumors (ATRTs) and is associated with poor clinical outcomes. Alisertib has demonstrated promising efficacy in multiple preclinical studies, which supported its advancement into clinical trials across various cancer types. However, alisertib has not met key efficacy endpoints primarily due to its poor biodistribution to tumors and inadequate penetration of biological barriers, including the blood-brain barrier (BBB). Our study aims to address these issues.Methods: To address the limitations of alisertib, we developed scL-ALI, a nanocomplex formulation designed to improve BBB penetration and to enhance tumor uptake of alisertib, to achieve higher effective intratumoral doses. Our new formulation of alisertib comprises a cationic liposome encapsulating the kinase inhibitor. This formulation incorporates an anti-transferrin receptor antibody fragment to enable efficient delivery into the central nervous system and facilitate tumor targeting. Here, we assessed the therapeutic efficacy of nano-formulated scL-ALI versus conventional alisertib utilizing patient-derived tumor cells and xenograft tumor models of various cancer types, including ATRT. Additionally, we investigated the potential synergistic effects of combining scL-ALI with radiation therapy, a standard treatment modality for brain tumors.Results: Compared to conventional alisertib, scL-ALI more effectively inhibited AURKA activity and enhanced tumor cell killing of multiple cancer cell lines. In mouse models of ATRT, glioblastoma, and lung cancer, scL-ALI significantly improved tumor growth inhibition relative to conventional unencapsulared alisertib. Furthermore, when combined with radiation therapy, scL-ALI produced further improved antitumor effects, leading to extended survival in ATRT-bearing mice.Conclusion: These findings highlight the superiority of scL-ALI in overcoming delivery barriers and enhancing therapeutic efficacy of alisertib, while possibly minimizing undesirable side effects in normal tissues. The scL-ALI nanocomplex shows enhanced therapeutic potential for treating AURKA-driven malignancies, particularly in combination with radiation therapy.Keywords: lipid nanoparticle, targeted nanodelivery, alisertib, aurora kinase A, atypical teratoid/rhabdoid tumor, blood-brain barrier