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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).

这个CCNE项目的中心目标是开发靶向组合的纳米技术