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

• 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
• 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

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(申请人提供)：这项拟议研究的目标是合成和验证多功能3T(靶向、跟踪和治疗)纳米细胞，用于修复急性肾缺血-再灌注损伤的血管。在这项研究中，纳米细胞被定义为纳米尺寸的药物包裹聚合体，结构类似于生物细胞。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药物，诱导血管正常化，最终改善各种急慢性和恶性疾病的治疗。经常有人提出，通过将这些药物与能够靶向和跟踪靶血管的载体相结合，可以显著改进这种血管正常化疗法。然而，这种多功能药物载体的发展一直受到独立控制靶向、跟踪和治疗功能的困难的困扰。我们假设，纳米细胞的3T功能可以通过(1)通过自组装过程整合到纳米细胞中，靶向模块，具有不同数目的烷基链和泄漏的内皮靶向寡肽的聚甘油，以及(2)通过原位封装进一步整合到纳米细胞中，通过磁共振成像(MRI)实现对纳米细胞的跟踪，从而独立地调节纳米细胞的3T功能。由此产生的3T纳米细胞将使我们能够显著改善血管正常化，同时使用MRI监测3T纳米细胞的治疗活动。我们将实现我们的目标，首先，通过自组装修饰和验证带有靶向模块的纳米细胞[目标1]；其次，将氧化铁纳米颗粒包裹在目标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，在目标2研究中创建的纳米细胞中加入使泄漏血管正常化的药物，特别是血管生成素1，并评估其治疗急性缺血再灌注损伤猪肾动脉损伤的功能[目标3]。在本研究中，烷基取代聚(2-羟乙基天冬酰胺)(PEHA)的聚合体填充了可生物降解的聚乙二醇纳米凝胶，将被用作纳米细胞。这项拟议的研究将通过生物材料小组[香港，伊利诺伊大学(UI)]、有机和聚合物合成小组[齐默尔曼，UI]以及生物成像和血管药物小组[Misra，Mayo Clinic]之间的广泛跨学科合作来实施。这项拟议的研究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。 与公共健康相关：这项拟议研究的成功完成将为组装多功能药物载体3T纳米细胞创造一种创新战略，允许独立调整靶向、跟踪和治疗功能。最终，这项研究将创造一种新的药物输送系统，它将显著提高诱导血管正常化的药物的治疗效果。总体而言，这项研究将极大地提高与血管渗漏有关的各种急性、慢性和恶性疾病患者的生活质量。