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点是肿瘤切除后复发 手术为了解决这一未满足的临床需求，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)功能性pH响应性“可膨胀”纳米颗粒（eNP）递送平台，其利用基本的 肿瘤的病理生理特性（例如，温和酸性的细胞外环境和高代谢率）， 引起组成和架构变化（例如，导致肿瘤特异性积聚 在细胞外和细胞内肿瘤环境中都具有增强的颗粒渗透和保留。 这种“基于材料的目标确定”方法克服了传统战略的局限性（例如，增强 渗透性和保留（EPR）效应，和基于抗体的靶向）。此外，还原的纳米颗粒 与抗体标记的纳米颗粒相比， 这是启动未来临床试验所必需的。 2)紫杉醇的可生物降解的药物-缀合物聚合物（PGC-PTX）的用途，当与紫杉醇共配制时， eNP聚合物将提供超高载药纳米颗粒。这些纳米颗粒提供了非常高的 载药量（40-70重量%），这将能够递送前所未有的局部剂量的药物。而且 紫杉醇的共价结合确保紫杉醇的延长（>60+天）递送，而爆发可忽略不计 释放（前10天<10%），同时避免全身毒性。 * 我们假设纳米颗粒递送平台的性质（即，PGC-PTX-eNPs）与材料- 基于靶向可以优化，以将超高局部剂量的紫杉醇递送至腹膜肿瘤， 从而防止间皮瘤癌症模型中手术切除后的肿瘤复发。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、细胞代谢、自噬和外科肿瘤学）来解决这一假设。的 这项五年计划的具体目标是：1）进行机理研究，以确定化学物质如何 PGC-PTX-eNPs的性质、纳米结构和药物掺入影响基于材料的靶向 功能性（例如，肿瘤特异性和细胞内运输）; 2）优化PGC-1的纳米颗粒制剂。 PTX-纳米粒对三种正常和耐药间皮瘤细胞的最大抗肿瘤作用 3）评估优化的PGC-PTX-eNP制剂以确定PGC-PTX-eNP制剂的生物相容性。 复发性间皮瘤PDX模型中的生物分布、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.