TUMOR SPECIFIC DELIVERY OF VERTICILLIN A OVERCOMES EPIGENETIC SILENCING RESPONSIBLE FOR DRUG RESISTANCE

摘要 这项提案描述了一种针对间皮瘤治疗失败的主要原因的创新解决方案：药物 抵抗。解决方案是控制和靶向传递一种新的表观遗传修饰剂- 维替西林A或其类似物--在化疗中重建化疗敏感性 通过重新表达表观遗传沉默的肿瘤抑制基因而产生的耐药肿瘤。不像其他小的 分子表观遗传剂，包括FDA批准的药物，即全球DNA甲基化和组蛋白 去乙酰酶抑制剂，轮状青霉素A选择性靶向H3K9me2/3。一种刺激响应性颗粒药物输送 采用独特的基于材料的靶向策略的系统被使用，以确保轮枝菌素和 化疗药物在腹膜肿瘤中定位和集中。这种对pH有反应的药物递送 系统利用肿瘤的基本病理生理特性(例如，轻度酸性的细胞外 环境和高代谢率)导致成分和结构变化(例如，颗粒肿胀 从0.1微米到1微米)，导致肿瘤特异性积聚。这种基于材料的目标定位方法 克服了传统策略的局限性(例如，通过增强渗透率和 保留效应和通过基于抗体的亲和力进行主动靶向)，同时提供了一个平台来提供这两者 疏水性药物和亲水性药物分别通过单乳剂和双乳剂。建议数 实验将检验这样一种假设，即用化疗药物输送轮状青霉素剂 (作为单一药物或与胶囊或免费药物联合使用的联合疗法) 间皮瘤肿瘤将克服耐药性并延长生存时间 维替西林或单独使用化疗药物。重要的是，关键的初步数据支持拟议的 研究，良好的表征材料和严格的实验设计，以及必要的交叉 学科合作和专业知识已经到位，以解决这一假设。这五个方面的具体目标是-- 一年的建议是：目标1.评价轮枝菌素A及其五个类似物在人体内的表观遗传学活性 从患者胸腔积液中收集间皮瘤细胞(MSTO-211H)和肿瘤细胞，以及 通过体外肝毒性、心脏毒性和线粒体毒性的毒性分析。目标2.优化 两种轮状青霉素与紫杉醇、顺铂或培美曲塞的联合制剂以达到最大限度 耐药间皮瘤细胞株和患者胸膜肿瘤细胞的细胞毒作用 积液。目的3.评估健康小鼠的毒性和PK和PD/最优配方在 耐药间皮瘤患者来源异种移植(PDX)小鼠模型。

ABSTRACT This proposal describes an innovative solution to a primary cause of treatment failure in mesothelioma: drug resistance. The solution is the controlled and targeted delivery of a novel epigenetic modifying agent – verticillin A or one of its analogs – which re-establishes chemotherapeutic susceptibility in chemotherapeutic resistant tumors via re-expression of epigenetically silenced tumor suppressor genes. Unlike other small molecule epigenetic agents, including FDA-approved drugs, which are global DNA methylation and histone deacetylase inhibitors, Verticillin A selectively targets H3K9me2/3. A stimuli-responsive particle drug delivery system employing a unique materials-based targeting strategy is used in order to ensure that the verticillin and chemotherapeutic agents localize and concentrate in peritoneal tumors. This pH-responsive drug delivery system leverages fundamental pathophysiological properties of tumors (e.g., mildly acidic extracellular environment and high metabolic rate) to induce compositional and architectural changes (e.g., particle swelling from 0.1 to 1 micron) resulting in tumor-specific accumulation. This materials-based targeting approach overcomes limitations of traditional strategies (e.g., passive targeting via the enhanced permeability and retention effect, and active targeting via antibody-based affinity) while providing a platform to deliver both hydrophobic and hydrophilic drugs via single- and double-emulsions, respectively. The proposed experiments will test the hypothesis that delivery of a verticillin agent with a chemotherapeutic (combination therapy either as single agents or co-formulation with encapsulated or free drug) to mesothelioma tumors will overcome drug resistance and extend survival compared to the delivery of verticillin or the chemotherapeutic alone. Importantly, key preliminary data are in support of the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross- disciplinary collaborations and expertise are in place to address this hypothesis. The specific aims of this five- year proposal are: Aim 1. Evaluate the epigenetic activity of verticillin A and five of its analogs in human mesothelioma cells (MSTO-211H) and tumor cells collected from patient pleural effusions as well as the toxicity profile via in vitro assays for hepatotoxicity, cardiotoxicity, and mitochondrial toxicity. Aim 2. Optimize the co-formulation of the two verticillin agents with paclitaxel, cisplatin, or pemetrexed to achieve the maximum cytotoxic effect in drug resistant mesothelioma cell lines and tumor cells collected from patient pleural effusions. Aim 3. Assess toxicity in healthy mice and PK and PD / efficacy of the optimized formulation in patient-derived xenograft (PDX) murine models of drug resistant mesothelioma.