Abstract 4470: Development of a nanoparticle formulation of an MMP-activated, tumor-specific prodrug with an enhanced therapeutic index for the treatment of breast cancer

Abstract Triple-negative breast cancer accounts for 20% of all breast cancer cases and has a poor prognosis due to the lack of targetable expression of specific hormone and growth factor receptors. Therefore, systemic chemotherapy is one of the main therapeutic options. However, a lack of tumor specificity results in systemic toxicity. A tumor-selective prodrug, such as ICT25881, could enhance the therapeutic index of the active drug. ICT2588 comprises a colchicine analogue as the active drug, which is conjugated to an MMP14-specific peptide sequence and an endcap to prevent non-specific degradation. MMP14 is widely expressed and functionally active in the tumor tissues and neo vasculature compared to healthy tissues where it is largely absent, thereby facilitating specific release of the active drug within the tumor microenvironment. Despite the therapeutic potential of ICT2588, a lack of aqueous solubility is a limitation. In this study we aim to optimize a nanoparticle formulation of ICT2588 using a lactic and glycolic acid (PLGA) based approach, to increase the aqueous solubility of ICT2588, while offering a controlled release system without additional toxicity.2 ICT2588 was synthesized and purified by semi-preparative HPLC. Nanoparticles were synthesized via nanoprecipitation and the formulations were optimized in terms of hydrodynamic diameter, zeta potential, and encapsulation efficiency. The evaluation of the ICT2588-PLGA formulations in an MDA-MB-231 triple negative breast cancer model will be reported, with the MMP14 overexpression validated by SDS PAGE and western blotting. The improvements in aqueous solubility will increase the therapeutic potential of ICT2588 and facilitate its translation towards clinical evaluation. 1.Atkinson JM, Falconer RA, Edwards DR, et al. Development of a novel tumor-targeted vascular disrupting agent activated by membrane-type matrix metalloproteinases. Cancer Research 2010;70(17):6902-6912, doi:10.1158/0008-5472.CAN-10-1440 2.Alsaab HO, Alharbi FD, Alhibs AS, et al. PLGA-Based Nanomedicine: History of Advancement and Development in Clinical Applications of Multiple Diseases. Pharmaceutics 2022;14(12):2728, doi:10.3390/pharmaceutics14122728 Citation Format: Zubeda Khatoon, Hannah L. Spencer, Huw S. Jones, Goreti R. Morais, Amalia R. Estrada, Robert A. Falconer. Development of a nanoparticle formulation of an MMP-activated, tumor-specific prodrug with an enhanced therapeutic index for the treatment of breast cancer [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 4470.