Biodegradable Polymerized Simvastatin

合成可降解聚合物通常用于药物输送和帮助组织再生。药物通常被封装在材料中，以便随后的扩散和/或降解介导释放。然而，封装的局限性包括有限的有效载荷和传送系统过早耗尽的可能性。为了延长药物的释放时间，药物被结合到聚合物上。药物可以通过连接剂附着在聚合物上，随后在裂解后释放分子，也可以在合成过程中被纳入聚合物主链。该项目的总体目标是开发和表征一种使用药物分子（在本例中是辛伐他汀）作为单体合成的聚合物。工作的假设是辛伐他汀的结构，与内酯部分的前药，是适合开环聚合。因此，聚合的辛伐他汀可以被加工成薄膜，通过水解降解释放出生物活性辛伐他汀分子，这些分子除了具有众所周知的降血脂作用外，还具有成骨、抗炎和血管生成的特性。目的1将开发和表征一种可降解的、聚合形式的辛伐他汀。考虑到这一目标，假设聚合物可以加工成释放辛伐他汀的可生物降解薄膜。目的2将研究辛伐他汀聚合膜是否在体内降解以刺激啮齿动物颅上植入模型的成骨。据推测，随着聚合物降解，生物活性辛伐他汀被释放以促进局部骨形成。如果本次探索性/开发奖提出的原理验证研究成功，该聚合物可能被制造成各种物理形式（例如，微球和组织工程支架），以利用辛伐他汀对骨骼和其他组织的多效作用，以及可能适用于他汀家族其他成员的方法。

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.