Abstract 300: An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast cancer

Based on data from the World Health Organization, breast cancer is the most common type of cancer among women, accounting for about 15% of all cancer-related deaths. Thus, new treatment options are urgently needed to decrease this mortality rate. In recent years, mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We recently reported that a 1,3-thiazolium-5-thiolate mesoionic compound (MIH 2.4Bl) inhibited oxidative phosphorylation in the MCF-7 breast cancer cell line compared to normal human mammary epithelial cells. Furthermore, MIH 2.4Bl induced cytotoxicity by activating autography-related proteins (Beclin-1 and ATG5) and cell cycle arrest at the G2/M phase. Based on our previous findings, MIH 2.4BI is a promising candidate for treating breast cancer. However, a major challenge facing cancer therapeutics is tumor delivery in vivo for the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improve the efficacy of chemotherapy agents. Nonetheless, drug delivery systems have been largely unexplored in the context of mesoionic compounds. Lipoproteins are ideal for carrying transporting lipophilic anti-cancer drugs and imaging agents as they circulate in the bloodstream for an extended period. In addition, the hydrophobic core of lipoprotein particles allows the incorporation of lipophilic components (including a number of anti-cancer agents). Reconstituted high-density lipoprotein (rHDL) mimics the structure and function of endogenous (i.e., human plasma) HDL and thus presents a potentially markedly improved therapeutic strategy for cancer drug delivery. Previous studies from our group have shown that a stable reconstituted synthetic rHDL-drug complex could be prepared by combining paclitaxel and other chemotherapy drugs using the natural lipid and protein components of circulating HDL via a novel procedure. In this preliminary work, we present an improved strategy of using a newly developed formulation of MIH 2.4BI compound with rHDL nanoparticles as the delivery agent. Also, physico-chemical characterization of the nanoparticles and cytotoxicity analyses using a panel of breast cancer cell lines were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. (D. Debnath and R.M. Petty contributed equally to this work) Citation Format: Dipti Debnath, R. Max Petty, Nirupama Sabnis, Jinmin Zhang, Andras G. Lacko, Helivaldo Diogenes Souza, Petronio Filgueiras Filho, J. Michael Mathis, Rafal Fudala. An improved strategy for delivering the mesoionic compound MIH 2.4Bl utilizing reconstituted high density nanoparticles (rHDL) in treating breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 300.