Abstract 1841: NanoGhost - A drug targeting system for treatment of solid tumors

Introduction: NanoGhosts (NGs) are nanovesicles derived from the cell membrane of human bone marrow mesenchymal stem cells (hBM-MSCs). NGs preserve MSCs cell membrane architecture and characteristics, thus harnessing MSCs’ innate targeting capability towards tumors. SN38 (a topoisomerase 1 inhibitor) is a highly potent anti-cancer drug with poor water solubility, low plasmatic stability, high systemic toxicity, and low bioavailability. SN38 is approved for colorectal cancer (CRC), and pancreatic cancer as the prodrug Irinotecan or as liposomal Irinotecan, respectively. It is also approved as the antibody drug conjugate sacituzumab govitecan-hziy for triple negative and HR+HER2- breast cancer and metastatic urothelial cancer. We aim to target SN38 to various solid tumors by utilizing the inherent tumor targeting capability of MSCs derived NGs while minimizing SN38 systemic exposure. Methods: MSCs derived NGs were loaded with SN38 using an NHS ester-activated linker. NGs bearing SN38 were tested for anti-cancer activity in vitro and in-vivo. Results: SN38-NHS linker reacted in excess of 20 equivalents to protein content in NGs suspension resulted in average loading of ∼0.08 µg SN38 per 1 µg NGs lipid. SN38 loaded NGs demonstrated relatively low leakage (of up to 34%) after up to 6 hr at 37°C in mouse serum. In vitro, SN38 loaded NGs inhibited proliferation of H460 lung cancer cells (IC50 of 1.6 µg/mL after 6 hr exposure). In vivo, IV administration of SN38 loaded NGs at a dose level of 5 mg/kg NGs lipid (∼0.4 mg/kg SN38), resulted in tumor growth inhibition of HCT116 CRC in mice, similar to the positive control given at a dose level that was ∼25 fold higher. Biodistribution analysis showed concentration of Cy7 labeled SN38-NGs at the tumor site while minimal-no retention in infiltrating organs. Maximal tolerated dose of SN38 loaded NGs was not yet achieved following administrating of up to 10 mg/kg, supporting use of higher levels in follow on studies. Summary: Our data support the use of NGs for targeting highly potent and toxic drugs with draggability barriers (such as SN38) to tumors. Citation Format: Haim Tsubery, Ziv Azoulay, Shir Weber, Michal Lulu, Limor Matzrafi, Yonatan Malca, Marcell Machluf, Osnat Bohana-Kashtan. NanoGhost - A drug targeting system for treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1841.