Abstract A029: Supramolecular Sequestration of Actinium-225 via Cyclodextrin Nanopolymers: A Novel Strategy for Targeted Alpha Therapy in Glioblastoma Multiforme

Abstract Glioblastoma is the most aggressive primary malignancy of the central nervous system and remains uniformly fatal despite multimodal treatment. Its diffuse infiltrative growth, extensive genetic heterogeneity, and partial protection by an intact blood–brain barrier limit the effectiveness of current therapies, including maximal surgical resection followed by chemoradiation. Residual infiltrative tumor cells that escape resection and irradiation inevitably drive local recurrence, underscoring the need for therapeutic strategies capable of eradicating microscopic disease while sparing normal neural tissue. Targeted alpha therapy represents a transformative approach to internal radiation delivery, leveraging the high–linear energy transfer and short path length of alpha particles to induce lethal DNA damage in cancer cells with minimal collateral injury. Actinium-225 is particularly attractive due to its multi-alpha decay cascade; however, its clinical application is constrained by recoil-driven release of radioactive daughter nuclides, resulting in systemic redistribution and dose-limiting renal toxicity. Conventional chelator-based systems are unable to adequately retain these recoiling daughters following alpha emission. In this study, we developed a cyclodextrin-based supramolecular nanocarrier designed to both deliver actinium-225 and retain its radioactive progeny. Cross-linked cyclodextrin nanoparticles were synthesized and functionalized with bifunctional chelators to enable stable actinium complexation, while the polymeric architecture provided a secondary containment barrier for recoiling daughter isotopes. Physicochemical characterization confirmed nanoparticle dimensions and surface properties compatible with tumor accumulation and potential transport across biological barriers. Radiochemical analyses demonstrated high labeling efficiency and sustained radionuclide stability. Importantly, the cyclodextrin nanocarrier exhibited significantly enhanced retention of actinium daughter nuclides compared with conventional chelated constructs. In vitro evaluation using glioblastoma cell lines and patient-derived tumor stem cells demonstrated potent, dose-dependent cytotoxicity at picomolar concentrations. Alpha irradiation produced dense clusters of DNA double-strand breaks that were independent of oxygen availability, supporting efficacy in hypoxic tumor regions characteristic of glioblastoma. Collectively, these results demonstrate that cyclodextrin-based nanocarriers substantially improve the therapeutic index of actinium-225–based targeted alpha therapy by mitigating daughter nuclide recoil while preserving potent cytotoxic activity. This platform offers a promising strategy for safe and effective treatment of infiltrative glioblastoma and supports further preclinical development toward targeted and localized alpha-radiotherapeutic interventions. This abstract was refined using generative artificial intelligence for language clarity; all scientific content was reviewed and approved by the author. Citation Format: Punna Suryadevara. Supramolecular Sequestration of Actinium-225 via Cyclodextrin Nanopolymers: A Novel Strategy for Targeted Alpha Therapy in Glioblastoma Multiforme [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;86(6_Suppl):Abstract nr A029.