Biocompatible Dendritic Polymers : In Vivo Applications

超出所提供的空间。越来越多的人期望靶向药物递送将极大地改善抗癌治疗。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、可生物降解的聚酯枝状聚合物。我们发现，在小鼠肿瘤模型中，一个树突上有聚乙二醇，另一个树突上有阿霉素的蝴蝶结结构是一种优越的药物载体。我们将在领结上附加其他药物，并测试治疗成功所需的最佳药物释放率的假设。我们还将采用最新的合成技术来设计新的树突聚合物，它们：a。同时递送两种药物；b。)有更大的有效载荷和靶向配体；c。)改进了药物附着和药物释放控制的联系。利用这些新的大分子，我们将测试以下与聚合物药物具有优越抗癌治疗作用的因素相关的假设。在特定目标1中，使用领结聚合物，我们将测试假设，即需要聚合物-药物在肿瘤中的摄取和聚合物的药物释放率的特定组合来优化抗肿瘤活性。我们假设所测试的每种抗癌药物的最佳释放率不同：阿霉素、顺式铂、喜树碱衍生物、氟嘧啶和紫杉醇。在具体目标2中，我们将设计将上述两种药物以确定的比例附着在单一聚合物上的合成路线。我们将使用这种“双桶”聚合物来测试假设，即与同时使用不同聚合物或作为游离药物一起使用的药物相比，同时使用两种适当选择的药物对啮齿动物实体肿瘤具有协同作用。在具体目标3中，我们将开发一种新的合成高分子量和具有各种结构的聚酯枝状聚合物。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结构来验证一个假设，即每个靶向配体需要大量的药物才能有效地靶向配体介导的药物。这项研究的完成将使各种显著改进的靶向治疗和诊断成像应用能够成功地应用于治疗人类癌症。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. 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 one 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 two 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 factorsthat 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 two 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 two 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. PERFORMANCE SITE ========================================Section End===========================================