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）：本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，用于修复因急性肾缺血再灌注损伤而受损的血管。在这项研究中，纳米细胞被定义为纳米尺寸的药物封装聚合物囊泡，其结构与生物细胞相似。临床研究表明，某些与内皮细胞结合的抗体和细胞因子可以用作诱导血管正常化的药物，并最终改善各种急性、慢性和恶性疾病的治疗。人们经常提出，通过将这些药物与能够靶向和跟踪目标血管的载体相结合，可以显着改善这种血管正常化疗法。然而，此类多功能药物载体的开发一直受到难以独立控制靶向、跟踪和治疗功能的困扰。我们假设纳米细胞的3T功能可以通过以下方式独立调节：（1）通过自组装过程、靶向模块、被不同数量的烷基链取代的聚（甘油）和渗漏内皮靶向寡肽整合到纳米细胞中，以及(2) 通过原位封装进一步将表面工程超顺磁性氧化铁纳米颗粒纳入纳米细胞中，从而能够通过磁共振成像 (MRI) 跟踪纳米细胞。由此产生的 3T 纳米细胞将使我们能够显着改善血管正常化，同时使用 MRI 监测 3T 纳米细胞的治疗活性。我们将首先通过自组装修改和验证具有靶向模块的纳米细胞来实现我们的目标[目标1]；其次，通过将氧化铁纳米颗粒封装在目标 1 研究中创建的纳米细胞中并验证其跟踪功能 [目标 2]；最后，在 Aim 2 研究中创建的纳米细胞中加入使渗漏血管正常化的药物，特别是血管生成素 1，并评估其治疗因急性缺血再灌注损伤而受损的猪肾动脉的功能 [目标 3]。在这项研究中，填充有可生物降解的聚乙二醇纳米凝胶的烷基取代的聚（2-羟乙基天冬酰胺）（PEHA）聚合物囊泡将被用作纳米细胞。这项拟议的研究将通过生物材料小组 [Kong，伊利诺伊大学 (UI)] 之间广泛的跨学科合作来实施；有机和聚合物合成组[Zimmerman，UI]；以及生物成像和血管医学组[米斯拉，梅奥诊所]。这项研究的结果预计将对生物工程和医学临床策略的研究产生重大影响，因为它不仅将创建一种组装多功能药物载体的创新策略，而且还将验证其改善血管正常化的功能。公共健康相关性：这项拟议研究的成功完成将创建一种组装多功能药物载体 3T 纳米细胞的创新策略，该策略允许独立调整靶向、跟踪和治疗功能。最终，这项研究将创建一种新型药物输送系统，该系统将显着提高诱导血管正常化的药物的治疗效果。总体而言，这项研究将极大地有助于改善患有与血管渗漏相关的各种急性、慢性和恶性疾病的人们的生活质量。