OPTIMIZATION OF NANOPARTICLE TUMOR-LOCALIZATION AND DRUG-LOADING FOR TREATING MESOTHELIOMA

优化纳米颗粒肿瘤定位和载药治疗间皮瘤

基本信息

批准号：
10083718
负责人：
Yolonda L Colson
金额：
$ 56.87万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083718
关键词：
3-Dimensional Abraxane Address Antibodies Architecture Autophagocytosis Autophagosome Biodistribution Biological Biological Assay Biological Process Cancer Model Carbon Dioxide Carbonates Cell Line Cellular Metabolic Process Clinical Clinical Trials Collaborations Data Disease Dose Drug Exposure Drug resistance Ensure Environment Ethanol Etiology Excision Experimental Designs Formulation Future Glycerol Glycolates Hydrophobicity Label 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 Polymer Chemistry Polymers Production Property Quality of life Radiolabeled Recurrence Residual Tumors 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 base biodegradable polymer cancer recurrence chemical property cohort cremophor EL drug efficacy extracellular improved in vivo innovation intraperitoneal metabolic rate multidisciplinary nanoarchitecture nanocrystal nanoengineering 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

项目摘要

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.

抽象的腹膜内间皮瘤治疗失败的一个常见问题是减瘤后癌症复发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“可膨胀”纳米颗粒 (eNP) 递送平台，利用基本原理肿瘤的病理生理学特性（例如弱酸性细胞外环境和高代谢率）诱导成分结构变化（例如颗粒膨胀），从而导致肿瘤特异性积累在细胞外和细胞内肿瘤环境中具有增强的颗粒渗透和保留。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，增强的渗透性和保留（EPR）效应，以及基于抗体的靶向）。与抗体标记的纳米颗粒相比，其复杂性将促进材料的大规模 GMP 生产对于启动未来的临床试验是必要的。 2) 使用可生物降解的紫杉醇药物共轭聚合物 (PGC-PTX)，当与 eNP 聚合物将提供超高载药量的纳米颗粒，这些纳米颗粒提供极高的载药量。载药量（40-70 wt%），这将能够输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的长时间（>60+天）递送，且爆发可忽略不计释放（前 10 天<10%），同时避免全身毒性。 *我们追求纳米粒子递送平台（即 PGC-PTX-eNPs）与材料的特性- 基于靶向可以进行优化，以将超高局部剂量的紫杉醇递送至腹膜肿瘤和重要的是，在间皮瘤癌症模型中预防手术切除后的肿瘤复发是关键。初步数据支持拟议的研究、充分表征的材料和严格的实验设计已经建立，并且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、自噬和肿瘤外科）已经可以解决这一假设。该五年提案的具体目标是： 1) 进行机械研究以确定化学如何 PGC-PTX-eNP 的特性、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- 的纳米颗粒配方 PTX-eNPs对三种正常和耐药间皮瘤细胞实现最大抗肿瘤效果线和六个患者样本；以及，3) 评估优化的 PGC-PTX-eNP 配方以确定复发性间皮瘤 PDX 模型中的生物分布、毒性、PK 和 PD/疗效。