Chemo-Enzymatic Synthesis of Unimolecular Polymeric Micelles for Drug Delivery

用于药物输送的单分子聚合物胶束的化学酶法合成

• 批准号: 7415029
• 负责人: DOUGLAS G HAYES
• 金额: $ 6.51万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7415029
• 关键词: Alcohols; Antibodies; Antioxidants; Arts; Attention; Behavior; Binding Sites; Biocompatible; Blood - brain barrier anatomy; Cell membrane; Chemical Structure; Chemicals; Cytoplasm; Data; Diffusion; Drug Delivery Systems; Enzymes; Esters; Ethers; Ethyl Ether; Ethylene Glycols; Figs - dietary; Food Additives; Freezing; Goals; Hydroxyl Radical; In Vitro; Investigation; Kinetics; Lead; Lectin; Left; Length; Lipase; Liposomes; Medical; Medical Imaging; Micelles; Molecular Weight; Numbers; Object Attachment; Oral; Organ; Pharmaceutical Preparations; Phase; Polyesters; Polymers; Preparation; Principal Investigator; Procedures; Process; Property; Protocols documentation; Publishing; Reaction; Research; Research Project Grants; Ricinoleic Acids; Scheme; Scientist; Series; Site; Small Intestines; Solutions; Solvents; Sterilization for infection control; Sterols; Structure; Technology; Temperature; Testing; Tocopherols; Toxicology; Upper arm; Water; base; biomaterial compatibility; chemical property; concept; controlled release; cost; ethylene glycol; hydroxyl group; improved; in vivo; middle lung lobe; novel; novel strategies; pentaerythritol; physical property; polyol; programs; prototype; receptor; ricinoleic acid; targeted delivery

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.

描述（由申请人提供）：拟议研究的目的是通过化学-酶促方法合成一系列新型单分子聚合物胶束（UPM），即，两亲性星星聚合物，以表征它们的化学结构，并进行它们作为疏水性药物的口服或肠胃外递送的载体的能力的体外测试。分子将由多元醇中心核组成，其羟基共价连接到聚（蓖麻油酸），聚（蓖麻油酸）又将通过pH稳定的醚和pH可降解的酯键与聚（乙二醇）共价键合，这将增强UPM用于靶向递送的适用性，例如，到小肠。与通常用于产生基于UPM、脂质体或树枝状聚合物的载体的程序相比，化学-酶促合成方法将涉及更简单和更安全的合成过程以及更低的操作和材料成本。预期所得的UPM在遇到温度变化（如在冷冻和灭菌期间发生的）或稀释（如在引入体内之后发生的）时将非常稳定。本研究的目的是进一步完善星形聚乙烯的酶法合成（蓖麻油酸）以提高每个分子的聚合物“臂”的数量，根据公开的方案通过碱可裂解键共价连接PEG，表征所得UPM的组成、结构、几何形状和pH控制的稳定性和降解性，并测试UPM的疏水药物溶解，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主要研究者（PI）获得概念验证数据，从而导致主要的“第二阶段”研究工作，检查UPM材料的体内能力以及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，拟议的研究将产生有用的载体，用于输送难溶于水的药物。与竞争技术相比，这些车辆将以更简单且可能更便宜的方式生产。它们将是高度生物相容的，将允许释放到体内的特定器官，并且将能够穿透药物递送的常见体内屏障，包括血脑屏障和细胞膜。