Biodegradable Polymerized Simvastatin

可生物降解的聚合辛伐他汀

• 批准号: 8622285
• 负责人: DAVID A. PULEO
• 金额: $ 18.63万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8622285
• 关键词: Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Award; Biocompatible Materials; Biological; Biomedical Engineering; Cells; Data; Defect; Development; Diffusion; Drug Delivery Systems; Drug usage; Encapsulated; Ethylene Glycols; Family; Film; Glycolates; Goals; Hydrolysis; Implant; Lactones; Local Anti-Infective Agents; Mediating; Methods; Microspheres; Modeling; Molecular Weight; Nanosphere; Nylons; Osteogenesis; Pharmaceutical Preparations; Polyanhydrides; Polyesters; Polymers; Process; Prodrugs; Property; Reaction; Research Project Grants; Rodent; Simvastatin; Site; Structure; System; Systemic Therapy; Testing; Tissue Engineering; Tissues; Trauma; Ursidae Family; Vertebral column; Work; biodegradable polymer; biomaterial compatibility; bone; cancer therapy; caprolactone; controlled release; copolymer; design; direct application; ethylene glycol; exhaustion; implantation; in vivo; member; monomer; multidisciplinary; osteogenic; particle; poly(lactic acid); polycarbonate; polymerization; premature; public health relevance; response; scaffold; tissue regeneration; tumor; uptake

DESCRIPTION: Synthetic degradable polymers are commonly used for drug delivery and to aid in tissue regeneration. Drugs are routinely encapsulated in the material for subsequent diffusion- and/or degradation-mediated release. Limitations with encapsulation, however, include limited payload and the potential for premature exhaustion of the delivery system. To prolong release, drugs have been conjugated to polymers. Drug can be attached to the polymer via a linker that subsequently releases the molecule following cleavage, or it can be incorporated into the polymeric backbone during synthesis. The overarching goal of this project is to develop and characterize a polymer synthesized using drug molecules, in the present case simvastatin, as monomers. The working hypothesis is that the structure of simvastatin, with a lactone moiety in the prodrug, is amenable to ring-opening polymerization. As such, polymerized simvastatin could then be processed into films that degrade by hydrolysis to release bioactive simvastatin molecules, which have osteogenic, anti-inflammatory, and angiogenic properties in addition to their well-known known hypolipidemic effects. Aim 1 will develop and characterize a degradable, polymerized form of simvastatin. With respect to this objective, it is hypothesized that the polymer can be processed into biodegradable films that release simvastatin. Aim 2 will investigate whether polymerized films of simvastatin degrade in vivo to stimulate osteogenesis in a rodent supracalvarial implantation model. It is hypothesized that, as the polymer degrades, bioactive simvastatin is released to enhance local bone formation. If the proof-of-principle studies proposed for this Exploratory/Developmental Award are successful, the polymer may be fabricated into a variety of physical forms (e.g., microspheres and tissue engineering scaffolds) to exploit the pleiotropic effects of simvastatin for bone and other tissue applications, as well as the methods potentially being applicable to other members of the statin family.

描述：合成可降解聚合物通常用于药物输送和帮助组织再生。药物通常包封在材料中，用于随后的扩散和/或降解介导的释放。然而，封装的局限性包括有限的有效载荷和递送系统过早耗尽的可能性。为了延长释放，药物已经与聚合物缀合。药物可以通过接头连接到聚合物上，随后在裂解后释放分子，或者它可以在合成过程中掺入聚合物主链中。 该项目的首要目标是开发和表征使用药物分子合成的聚合物，在目前的情况下，辛伐他汀作为单体。工作假设是，辛伐他汀的结构，与内酯部分的前药，是服从开环聚合。因此，聚合的辛伐他汀然后可以被加工成膜，该膜通过水解降解以释放生物活性辛伐他汀分子，该生物活性辛伐他汀分子除了其众所周知的降血脂作用之外还具有成骨、抗炎和血管生成特性。 目的1将开发和表征可降解的辛伐他汀聚合形式。关于这一目标，假设聚合物可以被加工成释放辛伐他汀的可生物降解的膜。目的2将研究辛伐他汀聚合膜在啮齿动物颅骨上种植模型中是否在体内降解以刺激成骨。据推测，随着聚合物降解，生物活性辛伐他汀被释放，以增强局部骨形成。 如果为该探索/发展奖提出的原理验证研究成功，则聚合物可以被制造成各种物理形式（例如，微球和组织工程支架）来开发辛伐他汀对骨和其它组织应用的多效性作用，以及潜在地适用于他汀家族其它成员的方法。