Biocompatible Dendritic Polymers : In Vivo Applications

我们描述了一种新的、稳健和经济的化学方法来制备具有窄多分散性的模块化可生物降解树枝状聚合物。这些新型材料有可能被用作聚合物药物载体，用于持续给药系统，或用于覆盖植入型生物工程医疗设备。我们将检验这样一种假设，即具有适当的分子质量、结构、药物和生物可逆药物连接的树枝状聚合物药物提供了改善的生物分布特性，从而导致比母药更好的抗癌药物治疗。在具体目标1中，我们将设计灵活的合成方法来制备生物相容的树枝状载体。我们开发了一种新的、快速、低成本地合成这些树枝状分子的方法，它消除了大多数树枝状大分子所需的繁琐的纯化步骤。我们将开发更多的合成方法，并优化分子结构、功能和模块化，这将极大地扩展这类有希望的多价药物载体的多功能性，用于靶向药物输送。在第二个具体目标中，我们将确定聚合物质量和结构对溶液中的物理化学性质和小鼠的药代动力学行为的影响。这些聚合物的物理性能将使用包括光散射测量、凝胶渗透色谱和扫描隧道显微镜在内的一系列表征技术来确定。随后将进行体外和体内实验，以确定附着物在荷瘤小鼠体内的细胞摄取、药代动力学、生物分布和肿瘤摄取。在特定的目标3中，我们将在异种实体瘤小鼠模型中确定聚合物抗癌药物对人乳腺癌的效力，作为聚合物属性、靶向配体、药物类型、载药量和药物释放机制的函数。预计具有适当分子量和结构的树枝状聚合物将更好地利用实体肿瘤中发现的增强的穿透和滞留现象，从而导致改进的抗肿瘤治疗。这项研究的成功将极大地提高我们设计聚合物药物载体的能力，这种载体使用其他聚合物合成方法将非常困难地制备，并使各种靶向治疗和成像应用的药代动力学特性得以优化。

We describe a new, robust and economical chemical approach to prepare modular biodegradable dendritic polymers with narrow polydispersities. These novel materials can potentially be used as polymeric drug carriers, in sustained drug delivery systems or to coat implantable bioengineered medical devices. We will test the hypothesis that dendritic polymeric drugs with the appropriate molecular weight, architecture, drug and bioreversible drug linkages, provide improved biodistribution properties that result in superior anti-cancer drug therapy compared to the parent drug. In specific aim number 1 we will devise flexible synthetic methods for the preparation of biocompatible dendritic carriers. We developed a new, rapid and low cost synthesis of these dendritic molecules that eliminate the need for the tedious purification steps required for most dendrimers. We will develop additional synthetic methods and optimize molecular architecture, functionality, and modularity that will greatly extend the versatility of this promising class of multivalent drug carriers for targeted drug delivery. In specific aim number 2, we will determine the effects of polymer mass and architecture on physico-chemical properties in solution and pharmacokinetic behavior in mice. The physical properties of these polymers will be determined using a combination of characterization techniques, including light scattering measurements, gel permeation chromatography, and STM. Subsequent in vitro and in vivo experiments will be conducted to determine the cellular uptake, pharmacokinetics, biodistribution and tumor uptake of attached materials in tumor-bearing mice. In specific aim number 3 we will determine the potency of polymeric- anticancer drugs against a human breast cancer in a xenograft solid tumor murine model as function of polymer attributes, targeting ligand, drug type, drug loading and drug release mechanism. It is anticipated that dendritic polymers with appropriate MW and architecture will better exploit the enhanced penetration and retention phenomenon found in solid tumors; hence lead to improved anti-tumor therapy. Success in this research will greatly improve our ability to design polymeric drug carriers that would be extremely difficult to prepare using other methods of polymer synthesis and that enable the optimization of the pharmacokinetic properties for a wide variety of targeted therapeutic and imaging applications.