Modular Assembly of 3T (Targeting, Tracking and Treating) Nanocells for Vascular

用于血管的 3T（靶向、跟踪和治疗）纳米细胞的模块化组装

基本信息

批准号：
8161467
负责人：
Hyunjoon Kong
金额：
$ 40.18万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8161467
关键词：
Acute Aneurysm Angiopoietin-1 Antibodies Binding Biocompatible Materials Biological Biomedical Engineering Blood Vessels Cell Adhesion Molecules Cells Chronic Clinic Clinical Clinical Data Clinical Research Collaborations Development Diffusion Disease Doctor of Philosophy Drug Carriers Drug Delivery Systems Encapsulated Endothelial Cells Endothelium Engineering Ensure Ethylene Glycols Family suidae Glycerol Goals Illinois Image In Situ Inflammation Inflammatory Injury Kidney Leukocytes Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Medicine Modeling Monitor NanoGel Oligopeptides Organ Pharmaceutical Preparations Plague Plasma Polymers Process Proteins Quality of life Reperfusion Injury Research Scheme Site Surface Therapeutic Tissues Transportation Treatment Efficacy Universities Vascular Diseases Vascular Endothelial Growth Factor Receptor-2 Vascular Permeabilities bioimaging cytokine ethylene glycol improved in vitro Assay in vivo innovation interdisciplinary collaboration interstitial iron oxide lung injury nanoparticle nanosized novel novel strategies particle poly(2-hydroxyethyl acrylate)pressure renal artery renal ischemia repaired self assembly tool

项目摘要

DESCRIPTION (provided by applicant): The objective of this proposed study is to synthesize and validate multifunctional 3T (targeting, tracking, and treating) nanocells for repair of blood vessels damaged by acute renal ischemic- reperfusion injury. For this study, nanocells are defined as nano-sized drug-encapsulating polymersomes, structurally similar to biological cells. Clinical studies suggest that certain antibodies and cytokines that bind to endothelial cells can be used as drugs that induce vascular normalization and ultimately improve treatments of various acute, chronic and malignant diseases. It has been often proposed that such vascular normalization therapies can be significantly improved by combining these drugs with carriers capable of targeting and tracking to the target blood vessels. However, the development of such multifunctional drug carriers has been plagued by difficulties in independently controlling targeting, tracking and treatment functions. We hypothesize that the 3T function of nanocells can be independently tuned by (1) integrating into the nanocell via self- assembly process, a targeting module, a poly (glycerol) substituted with varying numbers of alkyl chains and leaky endothelium-targeting oligopeptides, and (2) further incorporating into the nanocell via in situ encapsulation, surface-engineered super paramagnetic iron oxide nanoparticles that enable tracking of the nanocell via magnetic resonance imaging (MRI). The resulting 3T nanocells will allow us to significantly improve the vascular normalization while monitoring 3T nanocells' therapeutic activity using MRI. We will accomplish our goals, first, by modifying and validating the nanocells with targeting modules via self-assembly [Aim 1]; second, by encapsulating iron oxide nanoparticles in the nanocell created in the Aim 1 study and validating its tracking function [Aim 2]; and finally incorporating drugs that normalize leaky blood vessels, specifically Angiopoietin 1, in the nanocells created in the Aim 2 study and evaluating its function to treat porcine renal arteries damaged by acute ischemia-reperfusion injury [Aim 3]. In this study, polymersomes of alkyl-substituted poly (2-hydroxy ethyl aspartamide) (PEHA) filled with biodegradable poly (ethylene glycol) nanogels will be used as nanocells. This proposed study will be implemented through an extensive interdisciplinary collaboration between a biomaterials group [Kong, University of Illinois (UI)]; organic and polymer synthesis group [Zimmerman, UI]; and bioimaging and vascular medicine group [Misra, Mayo Clinic]. The results of this proposed study are expected to significantly impact research in bioengineering and clinical strategies in medicine, because it will not only create an innovative strategy for assembling multifunctional drug carriers, but also validate its functionality to improve vascular normalization. PUBLIC HEALTH RELEVANCE: The successful completion of this proposed study will create an innovative strategy for assembling a multifunctional drug carrier, 3T nanocell, which allows independent tuning of targeting, tracking and treating functions. Ultimately, this study will create a novel drug delivery system which will significantly improve the therapeutic efficacy of drugs that induce vascular normalization. Overall, this study will greatly contribute to improving peoples' quality of life who is suffering from a wide array of acute, chronic and malignant diseases related to leaky blood vessels.

描述（由申请人提供）：这项拟议的研究的目的是合成和验证多功能3T（靶向，跟踪和治疗）纳米细胞，以修复因急性肾脏缺血性融合损伤而受损的血管。在这项研究中，纳米细胞被定义为纳米大小的药物包裹的聚合物体，在结构上与生物细胞相似。临床研究表明，与内皮细胞结合的某些抗体和细胞因子可以用作诱导血管归一化的药物，并最终改善各种急性，慢性和恶性疾病的治疗方法。经常提出，通过将这些药物与能够靶向和跟踪到靶血管靶向和跟踪的携带者相结合，可以显着改善这种血管归一化疗法。但是，这种多功能药物载体的发展受到独立控制靶向，跟踪和治疗功能的困难。我们假设纳米细胞的3T函数可以通过（1）通过（1）通过自组装过程集成到纳米细胞中，该过程，一个靶向模块，一种用烷基链和漏水的漏水的甘油和漏水的内皮含量固定在site offerne的元素中，以及（2）在Site of ligopeption中取代的甘油，以及（2）进一步融合（2）通过磁共振成像（MRI）能够跟踪纳米球的氧化纳米颗粒。由此产生的3T纳米球将使我们能够使用MRI监测3T纳米细胞的治疗活性，从而显着改善血管归一化。首先，我们将通过自我组装[AIM 1]修改和验证纳米细胞来实现我们的目标；其次，通过封装在AIM 1研究中创建的纳米菌中氧化铁纳米颗粒并验证其跟踪功能[AIM 2]；最后，在AIM 2研究中创建的纳米细胞中纳入了使血管（特别是血管生成素1）归一化的药物，并评估其功能以治疗急性缺血 - 重新灌注损伤受损的猪肾动脉[AIM 3]。在这项研究中，含有可生物降解的聚（乙二醇）纳米凝胶的烷基取代的聚（2-羟基乙基乙基乙酰乙酯）（PEHA）的聚合物体将用作纳米球。这项拟议的研究将通过生物材料组[伊利诺伊大学（UI）]之间的广泛跨学科合作来实施；有机和聚合物合成组[Zimmerman，UI]；以及生物成像和血管医学组[Misra，Mayo Clinic]。预计这项拟议的研究的结果将显着影响医学生物工程和临床策略的研究，因为它不仅会为组装多功能药物携带者的创新策略，而且还验证了其功能以改善血管正常化。公共卫生相关性：这项拟议的研究的成功完成将创建一种创新的策略，用于组装多功能药物载体3T纳米赛，该纳米可独立调整靶向，跟踪和治疗功能。最终，这项研究将创建一个新型的药物输送系统，该系统将显着提高诱导血管归一化的药物的治疗功效。总体而言，这项研究将极大地有助于改善人民的生活质量，他们患有与泄漏血管有关的各种急性，慢性和恶性疾病。