Chemo-Enzymatic Synthesis of Unimolecular Polymeric Micelles for Drug Delivery

描述（由申请人提供）：拟议研究的目的是通过化学酶方法合成一系列新型单分子聚合物胶束（upm），即两亲星型聚合物，表征其化学结构，并进行体外测试，以确定其作为口服或外送疏水药物的载体的能力。分子将由多羟基醇中心核心组成，其羟基共价连接到聚（蓖麻油酸）上，聚（蓖麻油酸）又通过ph稳定的醚和ph可降解的酯键与聚（乙二醇）共价结合，这将增强upm用于靶向递送的适用性，例如小肠。与通常用于制造UPM、脂质体或树状聚合物载体的方法相比，化学酶合成方法将涉及更简单、更安全的合成过程，并降低操作和材料成本。预计所得到的upm在遇到温度变化时将非常稳定，如在冷冻和灭菌期间发生的温度变化，或稀释，如引入体内后发生的温度变化。该研究的目标是进一步完善星形聚（蓖麻油酸）的酶促合成，以提高每个分子的聚合“臂”数量，根据已发表的协议通过碱基可切割键共价连接PEG，表征合成的upm的组成、结构、几何形状、ph控制的稳定性和可降解性，并测试upm的疏水药物增溶性。扩散和ph触发释放（包括动力学），并测试其储存稳定性。拟议的研究项目将允许首席研究员（PI）获得概念验证数据，从而导致主要的“II期”研究工作，检查UPM材料的体内功能以及UPM结构与特定药物的溶解和释放特性之间的关系。如果成功的话，这项研究将生产出可用于递送难溶于水药物的有效载体。与竞争技术相比，这些车辆将以更简单、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，并且将能够穿透常见的体内药物传递障碍，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.