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

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

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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项目的核心目的是开发针对目标组合的纳米技术使用现有化合物具有次优的药物特性的药物治疗。基因组革命导致了大约320个分子靶标的鉴定，并尝试使用许多这些靶标的尝试面临着相当大的发展挑战（1、2）。最近，系统生物学的进步有助于确定这些新确定的靶标之间的协同途径，这些靶标可能会同时用于更有效的癌症治疗。纳米技术以时间调节的方式有效地传递多种药物或药物候选物的纳米技术可以潜在地克服迄今为止面临的发展挑战，并导致利用癌症基因组学和系统生物学的最大益处（3，4）。我们的早期工作由麻省理工学院的CCNE支持专注于工程针对的纳米颗粒，用于输送单个化学治疗剂（多西他赛）进行前列腺癌（PCA）治疗。使用工程组合过程通过自换材料可再现的靶向纳米颗粒库，我们筛选并鉴定出具有最佳生物物理化学特性的颗粒。现在，具有最佳特性的颗粒正在临床开发中并在2010年接近IND。额外的免费药物分子，我们将能够可重复地设计和表征能够输送2种药物的纳米颗粒； 2）通过将这些药物靶向纳米颗粒靶向癌细胞，我们可以实现协同的药物作用，这可以转化为更好功效和耐受性使其适合潜在的临床发展。本文中，我们建议开发用于靶向组合化疗的多达3种不同抗癌剂的共同传递的技术。作为一个模型癌，基于我们以前的努力，我们建议开发长循环的药物偶联的靶向纳米颗粒，以通过 PCA细胞。我们将旨在开发具有多达3种不同抗癌剂的靶向纳米颗粒，并在2014年将一种候选剂配方置于通往IND提交的开发路径上，为临床验证我们的临床验证我们的临床验证我们的临时性空体控制的组合化学疗法（TSCC）平台在患有激素的激素耐药性前列腺癌（HRPC）的患者中。