Targeted Nanoparticles for Tempospatially Controlled Combination Chemotherapy

这个CCNE项目的中心目标是开发纳米技术， 使用具有次优药物特性的现有化合物的药物疗法。基因组革命已经鉴定了约320种分子靶标，并且尝试在治疗上利用其中许多靶标面临相当大的发展挑战（1，2）。最近，系统生物学的进展有助于在这些新发现的靶点中识别协同途径，这些靶点可同时用于更有效的癌症治疗。用于以时间调节的方式向癌细胞有效递送多种药物或候选药物的纳米技术的开发可以潜在地克服迄今为止所面临的开发挑战，并导致利用癌症基因组学和系统生物学的最大益处（3，4）。我们的早期工作得到了麻省理工学院-哈佛大学CCNE的支持 专注于设计靶向纳米颗粒，用于递送用于前列腺癌（PCa）治疗的单一化疗剂（多西他赛）。将组合工艺用于工程 通过自组装的靶向纳米颗粒库，这是可重复的，我们筛选和鉴定具有最佳生物制药化学特性的颗粒。 具有最佳性能的颗粒目前正在临床开发中，并将于2010年获得IND。在该提议的上下文中，我们假设1）通过工程化和共混不同的药物官能化和配体官能化的聚合物，有或没有包封 另外的游离药物分子，我们将能够可重复地设计和表征能够递送2种或更多种药物的纳米颗粒;以及2）通过将这些载药纳米颗粒靶向癌细胞，我们可以实现协同药物效应，这可以转化为更好的治疗效果。 有效性和耐受性使其适合于潜在的临床开发。 在此，我们建议开发用于靶向组合化疗的最多3种不同抗癌剂的共递送技术。作为一个模型癌症，在我们以前的努力的基础上，我们建议开发长循环的药物缀合的靶向纳米颗粒，通过 PCa细胞。我们的目标是开发具有多达3种不同抗癌药物的靶向纳米颗粒，并将一种候选制剂置于2014年IND提交的开发路径上，为我们的时空控制联合化疗（TSCC）平台在激素难治性前列腺癌（HRPC）患者中的临床验证奠定基础。

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).