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

用于治疗间皮瘤的纳米颗粒肿瘤定位和载药优化

• 批准号: 10551854
• 负责人: Yolonda L Colson
• 金额: $ 50.01万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551854
• 关键词: 3-Dimensional; Abraxane; Address; Antibodies; Architecture; Autophagocytosis; Autophagosome; Binding; Biodistribution; Biological; Biological Assay; Cancer Model; Carbon Dioxide; Carbonates; Cell Line; Cellular Metabolic Process; Clinical; Clinical Trials; Collaborations; Data; Disease; Dose; Drug Exposure; Drug Kinetics; Drug resistance; Ensure; Environment; Ethanol; Etiology; Excision; Experimental Designs; Formulation; Future; Glycerol; Glycolates; Hydrophobicity; Lysosomes; Maintenance; Malignant Neoplasms; Malignant mesothelioma; Measures; Mediating; Mesothelioma; Metabolism; Modeling; Nanotechnology; Oncology; Operative Surgical Procedures; Ovarian; Paclitaxel; Pancreas; Particle Size; Patients; Pb clearance; Penetration; Peritoneal; Peritoneal Mesothelioma; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Polymer Chemistry; Polymers; Production; Property; Quality of life; Radiolabeled; Recurrence; Recurrent Malignant Neoplasm; Recurrent tumor; Residual Neoplasm; Route; Sampling; Solid; Surface; Surgical Oncology; Swelling; System; Therapeutic; Time; Tissues; Toxic effect; Treatment Failure; Tumor Debulking; Vertebral column; Weight; Work; Xenograft procedure; antitumor effect; biodegradable polymer; cancer recurrence; chemical property; cohort; cremophor EL; drug efficacy; extracellular; improved; in vivo; innovation; intraperitoneal; metabolic rate; multidisciplinary; nanoarchitecture; nanocrystal; nanoengineering; nanolabel; nanoparticle; nanoparticle delivery; novel; particle; patient derived xenograft model; peritoneal cancer; pharmacokinetics and pharmacodynamics; prevent; side effect; success; systemic toxicity; targeted delivery; trafficking; tumor; tumor specificity

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.

抽象的 腹膜内皮瘤的治疗失败点是癌症的复发。 外科手术。为了满足这种未满足的临床需求，提出了一个独特的基于纳米颗粒的解决方案： 1）功能性的pH响应性“扩展”纳米颗粒（ENP）输送平台，该平台利用基本 肿瘤的病理生理特性（例如，温和酸性细胞外环境和高代谢率） 诱导肿瘤特异性积累的组成和建筑变化（例如粒子肿胀） 在细胞外和细胞内肿瘤环境中均具有增强的颗粒穿透和保留。 这种“基于材料的目标”方法克服了传统策略的局限性（例如，增强 渗透性和保留效应（EPR）效应和基于抗体的靶向）。另外，纳米颗粒还原 与标有纳米颗粒的抗体相比，复杂性将促进大规模的GMP产生材料 对未来临床试验的主动性所必需的。 2）使用紫杉醇（PGC-PTX）的可生物降解的药物偶联物聚合物，该聚合物与该聚合物合成 ENP聚合物将提供超高的药物纳米颗粒。这些纳米颗粒提供了异常高的 药物加载（40-70 wt％），这将使能够递送前所未有的局部药物剂量。此外， 紫杉醇的共价结合可确保紫杉醇长时间（> 60多天）的紫杉醇延长（> 60多天） 释放（在前10天内<10％），同时避免系统性战术。 *我们假设纳米颗粒输送平台（即PGC-PTX-enps）的性质与材料 - 可以优化基于基于的靶向靶向，以将超高局部之前的紫杉醇剂量提供给腹膜肿瘤和 从而在间皮瘤癌症模型中预防手术切除后预防肿瘤复发。重要的是，关键 初步数据支持拟议的研究，特征良好的材料和严格的实验设计 建立并基本的跨学科合作和专业知识（纳米技术，聚合物 化学，细胞代谢，自噬和手术肿瘤学）已适当解决这一假设。 该五年建议的具体目的是：1）进行机械研究以确定化学 PGC-PTX-ENP的属性，纳米结构和药物掺入影响基于材料的靶向 功能（例如，肿瘤特异性和细胞内运输）； 2）优化PGC-的纳米颗粒公式 PTX-ENP可实现三个正常和耐药间皮瘤细胞的最大抗肿瘤作用 线和六个患者样本； 3）评估优化的PGC-PTX-ENP公式以确定 复发性间皮瘤的PDX模型中的生物分布，毒性，PK和PD/功效。