Abstract 307: Ponatinib loaded leukocyte-based nanoparticles: A new platform for treating osteosarcoma
Authors: Giordano Federica , Lenna Stefania , Rampado Riccardo , Baudo Gherardo , Massaro Matteo , Rivera Ashley , De Rosa Enrica , Yustein Jason T. , Taraballi Francesca 
Published: June 2022

Abstract
The introduction of targeted anticancer drugs has revolutionized treatment. Multi-tyrosine kinase inhibitors (TKIs) are potential therapeutics targeting specific signaling pathways that contribute to cancer progression, including sarcomas. Osteosarcoma is the most common pediatric tumor with a worldwide incidence of 3.4 cases/million annually but without effective treatment. Of the TKIs, Ponatinib demonstrated potent anti-tumor activity; however, it received an FDA black box warning for potential side effects. New treatment and delivery systems must be identified to use Ponatinib clinically. Our laboratory developed novel biomimetic nanoparticles (NPs) synthesized from activated leukocytes called Leukosomes. Leukosomes maintain leukocyte tropism towards inflamed endothelium and can encapsulate and effectively release Ponatinib. We aimed to validate Leukosome technology’s therapeutic potential to specifically target and inhibit primary murine osteosarcoma growth and reduce detrimental side effects. In a 3D sarcosphere model, we observed effective penetration and internalization of NPs in both murine (RF379, 577) and human patient derived xenograft (PDX94, PDX202) osteosarcoma cell lines. Leukosome exhibited 20% increased targeting versus control liposomes. Cell viability decreased 20% after treatment with Ponatinib IC50. Leukosome-Ponatinib IC50 also induced complete inhibition of murine sarcosphere formation and ~60-80% reduction of cell viability. We developed an osteosarcoma orthotopic mouse model by intratibial injection of murine F420 osteosarcoma cells. After 3 weeks, tumor was detected and the mice were injected with Ponatinib NPs. Leukosome showed increased tumor targeting and penetration 1 and 3 hours post-NP injection. Intravenous tail injection of Ponatinib was lethal due to drug-related toxic effects, while intraperitoneal injection of Ponatinib was well tolerated. Conversely, intravenous injection of Ponatinib-loaded NPs did not show toxic effects. In vivo efficacy studies demonstrated that 3 weeks of Ponatinib treatment (2 treatments/week) inhibited tumor growth and increased survival. Similar results were also observed after Leukosome Ponatinib treatment, despite 10 times less Ponatinib in NPs than in free drug. Overall, these results show that leukocyte-derived membrane proteins enhance the accumulation of Ponatinib at the tumor site and surrounding inflamed tissue. While limited Ponatinib encapsulation in NPs remains an open challenge, this formulation underlies the possibility of reducing drug dosage and side effects. Thus, suggest Leukosome’s translational potential as a new targeted drug delivery approach with better outcomes and fewer complications for osteosarcoma patients.
Citation Format: Federica Giordano, Stefania Lenna, Riccardo Rampado, Gherardo Baudo, Matteo Massaro, Ashley Rivera, Enrica De Rosa, Jason T. Yustein, Francesca Taraballi. Ponatinib loaded leukocyte-based nanoparticles: A new platform for treating osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 307.