Biocompatible Dendritic Polymers for in vivo Applications

描述（由申请人提供）：人们越来越期望靶向药物递送将大大改善抗癌治疗。为了加速实现这一目标，我们引入了一种新的合成方法来制备各种结构的模块化、可生物降解的聚酯树枝状聚合物。我们发现，蝴蝶结结构，PEG在一个树枝上，阿霉素在另一个树枝上，是一个上级药物载体在小鼠肿瘤模型。我们将把其他药物连接到蝴蝶结上，并测试最佳药物释放速率是治疗成功所必需的假设。我们还将采用最新的合成进展来设计新颖的树枝状聚合物，其：a.）同时递送2种药物; B.）具有更大的有效载荷和靶向配体; c.）具有改进的药物附着和药物控释的连接。使用这些新的大分子，我们将测试与有助于聚合物药物的上级抗癌治疗的因素相关的以下假设。在具体目标1中，使用蝴蝶结聚合物，我们将检验以下假设：需要肿瘤中聚合物-药物摄取和聚合物的药物释放速率的特定组合来优化抗肿瘤活性。我们假设，最佳释放率将不同的每一个抗癌药物测试：阿霉素，顺铂，喜树碱衍生物，氟嘧啶和紫杉醇。在具体目标2中，我们将设计用于将上述药物中的2种以限定的比例连接到单一聚合物的合成路线。我们将使用这种“双桶”聚合物来检验以下假设：与一起施用但在不同聚合物上或一起作为游离药物施用的药物相比，2种适当选择的药物同时递送至啮齿动物实体瘤是协同的。在具体目标3中，我们将开发一种新的合成高分子量和各种结构的聚酯树枝状聚合物的方法。我们将研究分子量/结构对药代动力学性质和靶向潜力的影响。我们使用更有前途的聚合物架构来测试的假设，每个靶向配体需要大量的药物有效的配体介导的药物靶向。这项研究的完成将使各种大幅改善的靶向治疗和诊断成像应用，可以成功地应用于治疗人类癌症。

DESCRIPTION (provided by applicant): There is a growing expectation that targeted drug delivery will greatly improve anticancer therapy. To accelerate attaining this goal, we introduced a new synthesis to prepare modular, biodegradable polyester dendritic polymers of various architectures. We showed that a Bow-tie architecture, with PEG on 1 dendron and doxorubicin on the other dendron, was a superior drug carrier in a murine tumor model. We will attach other drugs to the Bow-tie and test the hypothesis that optimal drug release rates are required for therapeutic success. We will also employ recent synthetic advances to devise novel dendritic polymers that: a.) Simultaneously deliver 2 drugs; b.) Have greater payloads and a targeting ligand; c.) Have improved linkages for drug attachment and controlled drug release. Using these novel macromolecules, we will test the following hypotheses related to the factors that contribute to superior anti-cancer therapy of the polymeric drug. In specific aim 1, using the bow-tie polymers, we will test the hypothesis that a specified combination of polymer-drug uptake in the tumor and drug release rate from the polymer is required to optimize anti-tumor activity. We hypothesize that the optimal release rate will differ for each anticancer agent tested: doxorubicin, cis-platinum, a camptothecin derivative, a fluoropyrimidine and paclitaxel. In specific aim 2, we will devise synthetic routes for attaching 2 of the above drugs, at defined ratios, to a single polymer. We will use this "double barrel" polymer to test the hypothesis that the simultaneous delivery to rodent solid tumors of 2 appropriately selected drugs is synergistic compared to the drugs administered together but on different polymers or together as free drugs. In specific aim 3, we will develop a new synthesis of polyester dendronized polymers of high molecular weight and with various architectures. We will examine the influence of molecular weight/architecture on the pharmacokinetic properties and targeting potential. We use the more promising polymer architectures to test the hypothesis that a high number of drugs per targeting ligand are required for effective ligand-mediated drug targeting. Completion of this research will enable a variety of substantially improved targeted therapies and diagnostic imaging applications that can be successfully applied to treat humans with cancer.