Targeted Drug Delivery via Microparticle-Drug Conjugates

通过微粒-药物偶联物进行靶向药物递送

基本信息

批准号：
6888082
负责人：
RICHARD A GEMEINHART
金额：
$ 15.24万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-01 至 2006-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6888082
关键词：
biological signal transduction blood aqueous barrier chemical conjugate drug delivery systems eye disorder chemotherapy fluorescence microscopy high performance liquid chromatography infrared spectrometry laboratory rat metalloendopeptidases microcapsule molecular shape neoplastic cell culture for noncancer research nuclear magnetic resonance spectroscopy particle polymers scanning electron microscopy ultraviolet spectrometry

项目摘要

DESCRIPTION (provided by applicant): Many diseases of the eye exist, and they are some of the most difficult diseases to treat. The blood-ocular barrier prevents many agents from penetrating the eye when administered orally or by I.V. injection. Many ocular diseases such as proliferative diabetic retinopathy, melanomas, retinoblastoma, and possibly cataracts are characterized by increases matrix-metalloprotease (MMP) and plasminogen activator activity. Both of these classes of natural cellular products are proteases used to promote the wound healing process. During disease progression, these proteases are excreted from diseased cells; the results of protease secretion are exacerbation of the disease state either by neovascularization or by cellular infiltration. A new system will be investigated that will have an impact upon any disease in which extracellular proteases are excreted. These proteases will be utilized to target drug delivery from drug-conjugated systems polymers. Not only will polymer-drug conjugates be utilized, but also microparticle-drug conjugates due to their increased size compared to polymer-drug conjugates. The microparticle-drug conjugates will have a peptide linker that is susceptible to matrix-metalloprotease digestion. Upon digestion by the MMP, free drug will be delivered allowing it to act upon the neighboring cells. The hypothesis to be tested is that targeting therapeutics to a molecular signal of a disease can improve the effectiveness and specificity of established therapeutics over that of the untargeted therapeutic. To test this hypothesis and complete the objectives, three specific aims have been set: 1) to develop and characterize conjugates of conventional therapeutics with polymeric microparticles, 2) to determine in vitro release and effectiveness of microparticle-drug conjugates, and 3) to determine in vivo release and effectiveness of microparticle-drug conjugates. Upon completion of this RO3 grant, sufficient data to conduct further research (RO1 grant) into the mechanisms and possibilities of the use of microparticles that are targeted to a specific molecular signal of an ocular disease .

描述（由申请人提供）：存在许多眼部疾病，并且它们是一些最难治疗的疾病。血眼屏障可防止许多药物在口服或静脉注射时渗入眼睛。注射。许多眼部疾病，如增殖性糖尿病视网膜病、黑色素瘤、视网膜母细胞瘤，可能还包括白内障，其特征是基质金属蛋白酶 (MMP) 和纤溶酶原激活剂活性增加。这两类天然细胞产品都是用于促进伤口愈合过程的蛋白酶。在疾病进展过程中，这些蛋白酶从患病细胞中排出；蛋白酶分泌的结果是通过新血管形成或细胞浸润加剧疾病状态。将研究一种新系统，该系统将对任何分泌细胞外蛋白酶的疾病产生影响。这些蛋白酶将用于从药物缀合系统聚合物靶向药物递送。不仅将利用聚合物-药物缀合物，而且还将利用微粒-药物缀合物，因为与聚合物-药物缀合物相比，微粒-药物缀合物的尺寸增加。微粒-药物缀合物将具有对基质金属蛋白酶消化敏感的肽接头。被 MMP 消化后，将释放游离药物，使其作用于邻近细胞。待测试的假设是，针对疾病的分子信号进行靶向治疗可以提高已建立的治疗方法相对于非靶向治疗方法的有效性和特异性。为了检验这一假设并完成目标，设定了三个具体目标：1）开发和表征传统疗法与聚合物微粒的缀合物，2）确定微粒-药物缀合物的体外释放和有效性，以及3）确定微粒-药物缀合物的体内释放和有效性。完成此 RO3 拨款后，将有足够的数据对针对眼部疾病的特定分子信号的微粒的使用机制和可能性进行进一步研究（RO1 拨款）。