OPTIMIZATION OF NANOPARTICLE TUMOR-LOCALIZATION AND DRUG-LOADINGFOR TREATING MESOTHELIOMA

摘要 腹膜内间皮瘤治疗失败的一个共同原因是去瘤后肿瘤复发。 做手术。为了解决这一未得到满足的临床需求，提出了一种独特的基于纳米颗粒的解决方案，该解决方案采用： 1)一种功能性的pH响应型纳米颗粒(ENP)输送平台，它利用基本的 肿瘤的病理生理特性(例如，细胞外环境中等酸性和高代谢率) 引起成分和结构变化(例如，颗粒肿胀)，从而导致肿瘤特异性聚集 增强了粒子在细胞外和细胞内肿瘤环境中的穿透性和滞留性。 这种基于材料的定向方法克服了传统策略的局限性(例如，增强的 渗透性和保留性(EPR)效应和基于抗体的靶向)。此外，还原后的纳米颗粒 与抗体标记的纳米颗粒相比，复杂性将有助于大规模、GMP材料的生产 这是启动未来临床试验所必需的。 2)使用可生物降解的紫杉醇药物偶联聚合物(PGC-PTX)，当与 ENP聚合物将提供超高载药量的纳米颗粒。这些纳米颗粒提供了异常高的 载药量(40-70wt%)，将能够提供前所未有的局部剂量的药物。此外， 紫杉醇的共价偶联可确保紫杉醇的长时间(60天以上)给药，且突发性可忽略不计 在避免全身毒性的同时释放(前10天10%)。 *我们假设纳米颗粒输送平台(即PGC-PTX-ENPs)与材料- 基于靶向的紫杉醇可以优化为将超高局部剂量的紫杉醇输送到腹膜肿瘤和 从而防止间皮瘤肿瘤模型手术切除后肿瘤复发。重要的是，Key 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 建立了必要的跨学科合作和专业知识(纳米技术、聚合物 化学、细胞新陈代谢、自噬和外科肿瘤学)来解决这一假说。这个 这个五年计划的具体目标是：1)进行机械研究，以确定化学物质如何 PGC-PTX-ENPs的性质、纳米结构和药物掺入对材料靶向性的影响 功能性(例如，肿瘤特异性和细胞内转运)；2)优化PGC的纳米颗粒配方 PTX-ENPs对三种正常和耐药间皮瘤细胞的最大抗肿瘤作用 以及，3)评估优化的PGC-PTX-ENP配方以确定 复发性间皮瘤PDX模型的生物分布、毒性、PK和PD/疗效。

ABSTRACT A common point of treatment failure in intraperitoneal mesothelioma is cancer recurrence following debulking surgery. To address this unmet clinical need, a unique nanoparticle-based solution is proposed which employs: 1) A functional pH-responsive “expansile” nanoparticle (eNP) delivery platform, which 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) that result in tumor-specific accumulation with enhanced particle penetration and retention both in the extracellular and intracellular tumoral environment. This “Materials-Based Targeting” approach overcomes limitations of traditional strategies (e.g., enhanced permeability and retention (EPR) effect, and antibody-based targeting). In addition, the reduced nanoparticle complexity, compared to antibody labeled nanoparticles, will facilitate large-scale, GMP production of material necessary for the initiation of future clinical trials. 2) Use of a biodegradable drug-conjugate polymer of paclitaxel (PGC-PTX) that, when co-formulated with the eNP polymer will afford an ultra-high drug-loaded nanoparticle. These nanoparticles provide exceptionally high drug loading (40-70 wt%) which will enable delivery of an unprecedented local dose of drug. Furthermore, the covalent conjugation of paclitaxel ensures prolonged (>60+ days) delivery of paclitaxel with negligible burst release (<10% in the first 10 days) while avoiding systemic toxicities. *We hypothesize that the properties of a nanoparticle delivery platform (i.e., PGC-PTX-eNPs) with Materials- Based Targeting can be optimized to deliver an ultra-high local dose of paclitaxel to peritoneal tumors and thereby prevent tumor recurrence following surgical resection in mesothelioma cancer models. Importantly, key preliminary data support the proposed studies, well-characterized materials and rigorous experimental designs are established, and essential cross-disciplinary collaborations and expertise (nanotechnology, polymer chemistry, cell metabolism, autophagy, and surgical oncology) are in place to address this hypothesis. The specific aims of this five year proposal are to: 1) Perform mechanistic studies to determine how chemical properties, nano-architecture and drug incorporation of PGC-PTX-eNPs impact the Materials-Based Targeting functionality (e.g., tumor-specificity and intracellular trafficking); 2) Optimize the nanoparticle formulation of PGC- PTX-eNPs to achieve the maximum antitumor effect against three normal and drug-resistant mesothelioma cell lines and six patient samples; and, 3) Evaluate the optimized PGC-PTX-eNP formulation to determine the biodistribution, toxicity, PK, and PD/efficacy in a PDX model of recurrent mesothelioma.