Nanocells for vascular normalization therapies

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大小的药物包封聚合体，结构类似于生物细胞。临床研究表明，与内皮细胞结合的某些抗体和细胞因子可作为诱导血管正常化的药物，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目标血管的载体联合使用，可以显著改善这种血管正常化治疗。然而，这种多功能药物载体的发展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、用不同数量的烷基链和渗漏的内皮靶向寡肽取代的聚（甘油）整合到纳米细胞中，以及(2)通过原位封装进一步整合到纳米细胞中，表面工程的超顺磁性氧化铁纳米颗粒可以通过磁共振成像（MRI）跟踪纳米细胞。由此产生的3T纳米细胞将使我们能够显著改善血管正常化，同时使用MRI监测3T纳米细胞的治疗活性。我们将完成我们的目标，首先，通过自组装修饰和验证靶向模块的纳米细胞[目标1]；第二，通过将氧化铁纳米颗粒封装在Aim 1研究中创建的纳米细胞中，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，并评估其治疗急性缺血再灌注损伤的猪肾动脉的功能[Aim 3]。在本研究中，烷基取代聚（2-羟基乙基阿斯巴酰胺）（PEHA）聚合体填充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之间的广泛跨学科合作来实施[Kong， University of Illinois (UI)]；有机高分子合成基团[Zimmerman， UI]；以及生物成像和血管医学小组[米斯拉，梅奥诊所]。本研究的结果将对生物工程和医学临床策略的研究产生重大影响，因为它不仅创造了一种组装多功能药物载体的创新策略，而且还验证了其改善血管正常化的功能。

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.