Chemo-Enzymatic Synthesis of Unimolecular Polymeric Micelles for Drug Delivery

描述(申请人提供)：拟议研究的目标是通过化学-酶方法合成一系列新型的单分子聚合物胶束(UPMS)，即两亲性星形聚合物，以表征其化学结构，并对其作为口服或肠外给药载体的能力进行体外测试。这些分子将由多元醇中心核组成，其羟基共价连接到聚(蓖麻酸)上，聚蓖麻酸将通过pH稳定的乙醚和pH可降解的酯键与聚乙二醇键共价键合，这将增强UPMS在靶向递送(例如，到小肠)方面的适用性。与通常用于制造UPM、脂质体或树枝状大分子的车辆相比，化学-酶合成方法将涉及更简单、更安全的合成过程，以及更低的操作和材料成本。预计，当遇到温度变化时，所得到的UPMS将非常稳定，如在冷冻和灭菌期间发生的，或在进入体内后发生的稀释。这项研究的目的是进一步改进酶法合成星形聚蓖麻酸，以增加每个分子的聚合物“臂”的数量，根据已发表的协议，通过碱基可裂解键共价连接聚乙二醇酯，表征所得到的UPMS的组成、结构、几何形状、pH控制的稳定性和降解性，并测试UPMS的疏水药物增溶、扩散和pH触发释放(包括动力学)，以及测试其储存稳定性。拟议的研究项目将使首席调查员(PI)能够获得概念验证数据，从而导致一项重大的“第二阶段”研究工作，检查芬欧蓝材料的体内能力以及UPM结构与特定药物的增溶和释放特性之间的关系。如果成功，这项拟议的研究将生产出有用的载体，用于运送难于溶于水的药物。与竞争对手的技术相比，这些汽车将以更简单、或许更便宜的方式生产。它们将具有高度的生物相容性，将允许释放到体内的特定器官，并将能够穿透体内常见的药物输送障碍，包括血脑屏障和细胞膜。

DESCRIPTION (provided by applicant): The objective of the proposed research is to synthesize by a chemo-enzymatic approach a series of novel unimolecular polymeric micelles (UPMs), i.e., amphiphilic star polymers, to characterize their chemical structure, and perform in vitro tests of their ability to act as vehicles for oral or parenternal delivery of hydrophobic drugs. The molecules will consist of a polyhydric alcohol central core, with its hydroxyls covalently attached to poly(ricinoleic acid), which in turn will be convalently bonded to poly(ethylene glycol) through pH-stable ether and pH-degradable ester bonds, which will enhance the UPMs applicability for targeted delivery, e.g., to the small intestine. A chemo-enzymatic synthetic approach will involve simpler and safer synthetic processes and lower operational and materials costs compared to procedures typically employed to create UPM-, liposome-, or dendrimer-based vehicles. It is anticipated that the resultant UPMs will be very stable when encountering temperature changes, as occur during freezing and sterilization, or dilution, as occurs subsequent to introduction into the body. The objectives of the proposed research are to further refine the enzymatic synthesis of star-poly(ricinoleic acid) in order to improve the number of polymeric "arms" per molecule, to covalently attach PEG though base-cleavable bonds according to published protocols, to characterize the composition, structure, geometry, and pH-controlled stability and degradability of the resultant UPMs, and to test the UPMs for hydrophobic drug solubilization, diffusional and pH-triggered release (including kinetics), and test for their storage stability. The proposed research project will allow the Principal Investigator (PI) to obtain proof-of-concept data, leading to a major "Phase II" research effort examining the in vivo capabilities of the UPM materials and the relationship between UPM structure and solubilization and release properties of specific drugs. If successful, the proposed research will produce useful vehicles for delivery of drugs that are poorly soluble in water. The vehicles will be produced in a simpler and perhaps less expensive manner compared to competing technologies. They will be highly biocompatible, will allow for release to a specific organ in the body, and will be able to penetrate through common in vivo barriers to drug delivery, including the blood-brain barrier and cell membranes.