Developing a nanoparticle platform for selective delivery of the anti-cancer drug MIH 2.4Bl to breast cancer cells

Date

2023

Authors

Debnath, Dipti
Petty, Roland
Kapic, Ammar
Sabnis, Nirupama
Lacko, Andras G.
da Silva Souza, Helivaldo Diógenes
de Athayde Filho, Petrônio Filgueiras
Mathis, J. Michael

ORCID

0000-0002-8996-4425 (Debnath, Dipti)
0000-0001-9168-7802 (Lacko, Andras G.)
0000-0001-5528-5195 (Mathis, J. Michael)

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Based on data from the World Health Organization, breast cancer is the most common 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 reported that a 1,3-thiazolium-5-thiolate mesoionic compound (MIH 2.4Bl) inhibited the growth of most of the breast cancer cell lines tested compared with normal human mammary epithelial cells. Treatment of MCF-7 breast cancer cells with MIH 2.4Bl resulted in alterations in cell cycle distribution with an increased proportion of cells in the G2/M phase compared with untreated cells. MCF-7 cells treated with MIH 2.4Bl also showed morphological changes consistent with apoptotic cell death. In addition, treating MCF-7 cells with MIH 2.4Bl resulted in a significant reduction in all mitochondrial respiratory parameters compared with the control cells, indicative of an overall decrease in mitochondrial membrane potential. These findings suggest that MIH 2.4Bl is a promising candidate for treating breast cancer. However, cancer therapy's primary challenge is 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 improving the efficacy of chemotherapy agents. However, drug delivery systems have been unexplored in mesoionic compounds. The reconstituted high-density lipoprotein (rHDL) nanoparticles have several advantages, including enhanced safety, efficacy, and biocompatibility. The payload, which is contained in the core of the HDL particle, is taken up by SR-B1 receptors, making this method particularly useful for targeted cancer chemotherapy. The upregulation of the SR-B1 receptor by tumor cells and tissues might be helpful in cancer treatment by specifically delivering drug-loaded nanoparticles to the tumors. In this preliminary work, we present an improved delivery strategy of a newly developed formulation of MIH 2.4Bl compound with rHDL nanoparticles as the delivery agent. Initial synthesis, optimization, physicochemical characterization, drug loading, and drug release assessment of the nanoparticles were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. To advance potential translational studies for monitoring in vitro drug delivery and colocalization of the drug in the cells, we have begun studies of the fluorescence properties of MIH 2.4Bl, using steady-state and time-resolved fluorescence techniques. The fluorescence characteristics of free MIH 2.4Bl was evaluated using UV/VIS and fluorescence spectroscopy. The steady-state and time-resolved measurements were designed to understand the optical properties of MIH 2.4Bl in solution for monitoring in vitro drug delivery and cellular colocalization. All samples, dissolved in various solvents, exhibited maximum absorbance between 440 and 480 nm; excitation at 440 nm elicited the highest emission at approximately 580 nm in methanol. These results may allow future detection and localization of MIH 2.4Bl in vitro and in vivo. Follow-up studies utilizing fluorescence confocal microscopy are anticipated to reveal drug accumulation's site(s) in situ and how cytotoxicity is induced in cancer cells.

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