Biocompatible Dendritic Polymers : In Vivo Applications

我们描述了一种新的，稳健的和经济的化学方法来制备模块化的生物可降解的枝状聚合物具有狭窄的多分散性。这些新型材料可以潜在地用作高分子药物载体，用于持续的药物输送系统或覆盖植入式生物工程医疗设备。我们将测试这样一个假设：具有适当分子量、结构、药物和生物可逆药物连接的树突聚合物药物，提供了更好的生物分布特性，与母体药物相比，具有更好的抗癌药物治疗效果。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性树突状载体。我们开发了一种新的，快速和低成本的合成这些树突分子的方法，消除了大多数树突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前途的多价药物载体的多功能性，用于靶向药物递送。在具体目标2中，我们将确定聚合物质量和结构对溶液中物理化学性质和小鼠药代动力学行为的影响。这些聚合物的物理性质将使用表征技术的组合来确定，包括光散射测量、凝胶渗透色谱和STM。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。在具体目标3中，我们将根据聚合物属性、靶向配体、药物类型、药物负载和药物释放机制，在异种移植实体瘤小鼠模型中确定聚合物抗癌药物对抗人类乳腺癌的效力。预计具有合适分子量和结构的枝状聚合物将更好地利用实体肿瘤中发现的增强渗透和保留现象；从而导致抗肿瘤治疗的改进。这项研究的成功将极大地提高我们设计高分子药物载体的能力，这将是使用其他聚合物合成方法难以制备的，并且能够优化药物的药代动力学特性，用于各种靶向治疗和成像应用。

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.