Targeted Nanoparticles for Tempospatially Controlled Combination Chemotherapy

用于时空控制联合化疗的靶向纳米颗粒

基本信息

批准号：
7983673
负责人：
ROBERT Samuel LANGER
金额：
$ 90.15万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
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：
2010-09-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7983673
关键词：
Amino Acids Antineoplastic Agents Biodistribution CCNE1 gene Cancer Model Clinical Combination Drug Therapy Development Drug Delivery Systems Drug Formulations Drug Kinetics Drug usage Engineering Evaluation Genomics In Vitro Libraries Ligands Malignant Neoplasms Malignant neoplasm of prostate Modeling Molecular Target Mus Nanotechnology Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Polymers Process Property Prostate Cancer therapy Rattus Rodent Screening procedure Staging Systems Biology Technology Toxic effect Toxicokinetics Translating Validation Work Xenograft Model cancer cell cancer genomics chemotherapeutic agent combinatorial docetaxel drug candidate drug development effective therapy functional group hormone refractory prostate cancer in vivo manufacturing process nanoparticle nonhuman primate particle pre-clinical subcutaneous tumor uptake

项目摘要

The central aim of this CCNE project is to develop nanotechnologies for targeted combination pharmacotherapy using existing compounds with suboptimal pharmaceutical properties. The genomic revolution has resulted in the identification of approximately ~320 molecular targets and attempts to therapeutically utilize many of these have faced considerable development challenges (1, 2). More recently, advances in systems biology have aided in identifying synergistic pathways among these newly identified targets that may be concurrently utilized for more effective treatment of cancers. The development of nanotechnologies for effective delivery of multiple drugs or drug candidates in a temporally regulated manner to cancer cells can potentially overcome the development challenges faced to date, and result in harnessing the maximal benefits of cancer genomics and systems biology (3, 4). Our early work supported by the MIT-Harvard CCNE focused on engineering targeted nanoparticles for delivery of a single chemotherapeutic agent (docetaxel) for prostate cancer (PCa) therapy. Using a combinatorial process for engineering libraries of targeted nanoparticles by selfassembly, which is reproducible, we screened and Identified particles with optimal biophysicochemical properties. Particles with optimal properties are now in clinical development and approaching an IND in 2010./n the context of this proposal we hypothesize that 1) by engineering and blending distinct drugfunctionalized and ligand-functionalized polymers, with or without encapsulation of additional free drug molecules, we will be able to reproducibly engineer and characterize nanoparticles capable of delivering 2 or more drugs; and 2) by targeting these drug loaded nanoparticles to cancer cells we can achieve synergistic drug effects which may translate to better efficacy and tolerability making them suitable for potential clinical development. Herein we propose to develop technologies for co-delivery of up to 3 distinct anticancer agents for targeted combination chemotherapy. As a model cancer, building on our previous efforts, we propose to develop long circulating drug-conjugated targeted nanoparticles for differential uptake by PCa cells. We will aim to develop targeted nanoparticles with up to 3 distinct anticancer agents and place one candidate formulation on a development path toward an IND submission in 2014, setting the stage for clinical validation of our TempoSpatially-controlled Combination Chemotherapy (TSCC) platform in patients with hormone refractory prostate cancer (HRPC).

该 CCNE 项目的中心目标是开发用于靶向组合的纳米技术使用具有次优药物特性的现有化合物进行药物治疗。基因组革命已导致约 320 个分子靶标的鉴定，并且在治疗上利用其中许多分子靶标的尝试面临着相当大的开发挑战 (1, 2)。最近，系统生物学的进展有助于确定这些新发现的靶点之间的协同途径，这些途径可以同时用于更有效地治疗癌症。开发纳米技术以时间调控的方式有效地将多种药物或候选药物递送至癌细胞，有可能克服迄今为止面临的开发挑战，并充分发挥癌症基因组学和系统生物学的最大优势 (3, 4)。我们的早期工作得到了麻省理工学院-哈佛大学 CCNE 的支持专注于工程靶向纳米粒子，用于输送单一化疗药物（多西紫杉醇）用于前列腺癌（PCa）治疗。使用组合过程进行工程通过自组装形成可重复的靶向纳米颗粒库，我们筛选并鉴定了具有最佳生物物理化学特性的颗粒。具有最佳性能的颗粒目前正处于临床开发阶段，并于 2010 年接近 IND。/在本提案的背景下，我们假设 1) 通过设计和混合不同的药物功能化和配体功能化聚合物，无论有或没有封装额外的游离药物分子，我们将能够可重复地设计和表征能够输送 2 种或更多药物的纳米颗粒； 2）通过将这些载药纳米粒子靶向癌细胞，我们可以实现协同药物效应，这可能会转化为更好的效果功效和耐受性使它们适合潜在的临床开发。在此，我们建议开发联合输送多达 3 种不同抗癌药物的技术，用于靶向联合化疗。作为一种癌症模型，在我们之前的努力的基础上，我们建议开发长期循环的药物缀合的靶向纳米粒子，以实现不同的摄取前列腺癌细胞。我们的目标是开发含有多达 3 种不同抗癌药物的靶向纳米粒子，并将一种候选制剂置于 2014 年 IND 提交的开发道路上，为我们的 TempoSpatially 控制联合化疗 (TSCC) 平台在癌症患者中的临床验证奠定基础。激素难治性前列腺癌（HRPC）。