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

D. Debnath, R. Petty, N. Sabnis, Jinmin Zhang, A. Lacko, H. Souza, P. F. Filho, J. Mathis, R. Fudała
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Abstract

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.
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摘要300:利用重组高密度纳米颗粒(rHDL)递送介离子化合物MIH 2.4Bl治疗乳腺癌的改进策略
根据世界卫生组织的数据,乳腺癌是女性中最常见的癌症类型,约占所有癌症相关死亡人数的15%。因此,迫切需要新的治疗方案来降低这一死亡率。近年来,介离子化合物由于其独特的结构和反应性质,在抗癌方面显示出很大的潜力。我们最近报道了一种1,3-噻唑-5-硫酸盐介离子化合物(MIH 2.4Bl)在MCF-7乳腺癌细胞系中抑制氧化磷酸化,与正常人乳腺上皮细胞相比。此外,MIH 2.4Bl通过激活签名相关蛋白(Beclin-1和ATG5)和细胞周期阻滞在G2/M期诱导细胞毒性。根据我们之前的研究结果,MIH 2.4BI是治疗乳腺癌的有希望的候选药物。然而,癌症治疗面临的一个主要挑战是肿瘤的体内递送,以选择性地破坏恶性细胞,同时保留正常细胞以保持组织的完整性。开发和使用给药系统是公认的提高化疗药物疗效的方法。尽管如此,在介离子化合物的背景下,药物输送系统在很大程度上尚未被探索。脂蛋白是理想的运输亲脂性抗癌药物和显像剂,因为它们在血液中循环了很长一段时间。此外,脂蛋白颗粒的疏水核心允许掺入亲脂成分(包括一些抗癌剂)。重组高密度脂蛋白(rHDL)模仿内源性(即人血浆)高密度脂蛋白的结构和功能,因此提出了一种潜在的显著改善癌症药物输送的治疗策略。我们小组先前的研究表明,通过一种新的方法,利用循环HDL的天然脂质和蛋白质成分,将紫杉醇和其他化疗药物结合,可以制备稳定的合成rhdl -药物复合物。在这项初步工作中,我们提出了一种改进的策略,使用新开发的以rHDL纳米颗粒作为递送剂的MIH 2.4BI化合物配方。此外,纳米颗粒的物理化学特性和细胞毒性分析使用一组乳腺癌细胞系进行。这些研究支持MIH 2.4Bl在治疗乳腺癌中的潜在治疗用途。(D. Debnath和R.M. Petty对本文贡献相同)引文格式:Dipti Debnath, R. Max Petty, Nirupama Sabnis, Jinmin Zhang, Andras G. Lacko, Helivaldo Diogenes Souza, Petronio Filgueiras Filho, J. Michael Mathis, Rafal Fudala。利用重组高密度纳米颗粒(rHDL)递送介离子化合物MIH 2.4Bl治疗乳腺癌的改进策略[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):摘要第300期。
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