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Abstract 2883: A transformable delivery system for the effective treatment of pediatric central nervous system tumors

Malignancies of the central nervous system (CNS) are the most common type of solid tumor affecting children and a leading cause of cancer-related death in children. With the deterioration of brain tumors, blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB) with poor permeability, and relatively weak enhanced permeability and retention effect become major obstacles in delivering therapeutics to brain tumors. Vincristine (VCR) is a mainstay of treatment of a variety of cancers including brain tumors due to its well-defined mechanism of action and demonstrated anticancer activity. However, the clinical application of VCR in brain tumors was limited by its neurotoxicity and inability to penetrate BBB/BBTB resulting in unsatisfactory anti-cancer efficacy. In this project, we developed a transformable nanoparticle, named Ninja-nanoparticle, which is capable overcoming several important barriers for drug delivery to CNS tumors resulting in better efficacy and toxicity profile. Ninja-NP was stable during circulation due to crosslinking and could transpass BBB/BBTB through glucose receptor-mediated transcytosis. Ninja-NP could further transform into smaller nanoparticle upon encountering acidic microenvironment and revealed hidden moiety to target tumor surface overexpressed sialic acid. Ninja-NP employed a unique strategy which could sequentially target BBB/BBTB and brain tumor cells. Our study confirmed that VCR loaded Ninja-NP significantly accumulated at the orthotopic brain tumor sites, and exhibited superior anti-cancer efficacy in orthotopic diffuse intrinsic pontine glioma (DIPG), the most deadly pediatric CNS tumor, then free VCR or Liposomal VCR with limited systemic toxicity. Ninja-NP addresses multiple challenges for CNS tumor treatment and exhibits great potential to be translated into an effective theranostic nano-platform which could be seamlessly integrated into standard human brain tumor management (imaging-guided drug delivery) with reduced long term toxicity. Citation Format: Tzu-yin Lin. A transformable delivery system for the effective treatment of pediatric central nervous system tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2883.