EGFR-Targeted Nanoemulsions for Imaging and Therapy of Ovarian Cancer

用于卵巢癌成像和治疗的 EGFR 靶向纳米乳剂

基本信息

批准号：
7805319
负责人：
Timothy Patrick Coleman
金额：
$ 14.99万
依托单位：
NEMUCORE MEDICAL INNOVATIONS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-21 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7805319
关键词：
Abdomen Address Adverse effects Apoptosis Apoptotic Biodistribution Biological Assay Biological Availability CA-125 Antigen Cancer Model Cancer Patient Carboplatin Cells Ceramides Cessation of life Charge Clinical Trials Combined Modality Therapy Contrast Media Data Diagnostic Diagnostic Procedure Disease Disease Progression Disease regression Disease remission Dose Drug Formulations Drug Kinetics Engineering Epidermal Growth Factor Receptor Epithelial ovarian cancer Failure Female Gadolinium Goals Human Image In Vitro In complete remission Injection of therapeutic agent Lead Location Magnetic Resonance Imaging Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Monitor Morphology Mus N-caproylsphingosine Newly Diagnosed Oils Outcome Ovarian Adenocarcinoma Paclitaxel Particle Size Patients Peptides Pharmaceutical Preparations Phase Plasma Platinum Positioning Attribute Relapse Rodent Safety Staging Surface Suspension substance Suspensions Technology Therapeutic Time Toxic effect Treatment Efficacy United States Water X-Ray Computed Tomography Xenograft Model Xenograft procedure aqueous base cancer cell clinical practice cytotoxicity improved in vivo intraperitoneal manufacturing scale-up mouse model nanoemulsion nanoparticle neoplastic cell novel ovarian neoplasm particle phase 2 study physical property preclinical study public health relevance receptor binding targeted delivery tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Today 70% of patients with advanced ovarian cancer will achieve clinically complete remission with front line treatments of carboplatin and paclitaxel, unfortunately a majority these patients are destined to relapse and eventually die of disease within 12-18 months due to a persistence of chemoresistant cells. Diagnostic techniques for ovarian cancer include normal exam, monitoring CA-125 level and CT-scans all capable of observing gross changes in disease progression but are less sensitive at quantitating the number or location of chemoresistant cells. Our overarching strategy addresses the major failures of the front line therapy and diagnostics by using multifunctional nanoemulsions to target, image, and enhance cytotoxicity to simultaneously eradicate chemosensitive and chemoresistant tumor cells. Extending our positive rodent studies combining targeting, imaging and therapeutic in a single vehicle, these proposed studies will focus on engineering multifunctional nanoemulsions capable of: 1) Targeting EGFR expressing cells which is found on majority of ovarian cancers; 2) imaging disease regression or progression by delivering DPTA-Gd3+, an magnetic resonance imaging (MRI) contrast agent, directly to tumor cells; and 3) enhance the cytotoxicity of carboplatin by targeting but also by co-delivering the pro-apoptotic molecule C6-ceramide, shown to reestablish key apoptosis pathways to overcome chemoresistance. Preclinical studies will be carried out in human ovarian adenocarcinoma xenograft models in female nu/nu mice to identify key pharmacokinetics parameters, efficacy, and ability to image delivery efficiency and disease progression using MRI. Successful completion of these studies will guide Phase II studies to generate safety, pharmacokinetics, efficacy and scale-up manufacturing data to advance to clinical trials. Phase I outcomes will additionally encourage exploration of enhancing the targeted delivery of other chemotherapeutic drugs or other compounds that had not previously been evaluated clinically due to physical properties, bioavailability or toxicities. PUBLIC HEALTH RELEVANCE: An estimated 22,000 new cases in 2008 and approximately 15,000 deaths in the United States, epithelial ovarian cancer is the most lethal of gynecologic cancers, due to its propensity to spread into the upper abdomen and beyond. Frontline lead to clinically complete remission in over 70% of patients, however typically within 12-18 months those patients relapse due to chemoresistant cells. Diagnostic techniques for ovarian cancer include normal exam, monitoring CA-125 level and CT-scans all capable of observing gross changes in disease progression but are less sensitive at quantitating the number or location of chemoresistant cells. Our overarching strategy addresses the major failures of the front line therapy and diagnostics by using multifunctional nanoemulsions to target, image, and enhance cytotoxicity to simultaneously eradicate chemosensitive and chemoresistant tumor cells.

描述（由申请人提供）：如今，70% 的晚期卵巢癌患者通过卡铂和紫杉醇一线治疗将实现临床完全缓解，不幸的是，这些患者中的大多数注定会复发，并最终在 12-18 个月内死于疾病。导致耐药细胞的持续存在。卵巢癌的诊断技术包括正常检查、监测 CA-125 水平和 CT 扫描，所有这些都能够观察疾病进展的总体变化，但在定量化疗耐药细胞的数量或位置方面不太敏感。我们的总体策略通过使用多功能纳米乳剂来靶向、成像和增强细胞毒性，以同时根除化疗敏感和化疗耐药的肿瘤细胞，从而解决一线治疗和诊断的主要失败问题。扩展我们在单一载体中结合靶向、成像和治疗的阳性啮齿动物研究，这些拟议的研究将重点关注工程多功能纳米乳剂，该纳米乳剂能够：1）靶向大多数卵巢癌中发现的 EGFR 表达细胞； 2) 通过将 DPTA-Gd3+（一种磁共振成像 (MRI) 造影剂）直接递送至肿瘤细胞，对疾病消退或进展进行成像； 3) 通过靶向和共同递送促凋亡分子 C6-神经酰胺来增强卡铂的细胞毒性，该分子被证明可以重建关键的凋亡途径以克服化疗耐药性。临床前研究将在雌性 nu/nu 小鼠的人类卵巢腺癌异种移植模型中进行，以确定关键的药代动力学参数、功效以及使用 MRI 成像递送效率和疾病进展的能力。这些研究的成功完成将指导二期研究，以产生安全性、药代动力学、功效和扩大生产数据，以推进临床试验。第一阶段的结果还将鼓励探索增强其他化疗药物或其他化合物的靶向递送，这些药物或化合物之前由于物理性质、生物利用度或毒性而未经过临床评估。公共健康相关性：据估计，2008 年美国有 22,000 例新病例，约 15,000 例死亡，上皮性卵巢癌是最致命的妇科癌症，因为它易于扩散到上腹部及以上。前线疗法使超过 70% 的患者获得临床完全缓解，但这些患者通常会在 12-18 个月内因化疗耐药细胞而复发。卵巢癌的诊断技术包括正常检查、监测 CA-125 水平和 CT 扫描，所有这些都能够观察疾病进展的总体变化，但在定量化疗耐药细胞的数量或位置方面不太敏感。我们的总体策略通过使用多功能纳米乳剂来靶向、成像和增强细胞毒性，以同时根除化疗敏感和化疗耐药的肿瘤细胞，从而解决一线治疗和诊断的主要失败问题。