Nanocells for vascular normalization therapies

描述（由申请人提供）：本拟议研究的目的是合成和验证多功能3 T（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封装聚合物囊泡，结构上类似于生物细胞。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。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组合，可以显著改善这种血管正常化疗法。然而，这种多功能药物载体的开发一直受到难以独立控制靶向、追踪和治疗功能的困扰。我们假设纳米细胞的3 T功能可以通过以下方式独立地调节：（1）通过自组装过程将靶向模块、多聚腺苷酸（poly-1）、聚腺苷酸（poly-2）和聚腺苷酸（poly-3）整合到纳米细胞中。（甘油）被不同数量的烷基链和泄漏的内皮靶向寡肽取代，和（2）通过原位包封进一步掺入纳米细胞中，表面工程化的超顺磁性氧化铁纳米颗粒，能够通过磁共振成像（MRI）跟踪纳米细胞。由此产生的3 T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3 T纳米细胞的治疗活性。我们将实现我们的目标，首先，通过自组装修饰和验证具有靶向模块的纳米细胞[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];最后加入使渗漏血管正常化的药物，特别是血管生成素1，目的2研究中创建的纳米细胞中，并评估其治疗急性缺血-再灌注损伤的猪肾动脉的功能[目的3]。在这项研究中，烷基取代的聚（2-羟乙基乙酰胺）（PEHA）填充可生物降解的聚（乙二醇）纳米凝胶的聚合物囊泡将被用作纳米细胞。本拟定研究将通过生物材料组[Kong，伊利诺伊大学（UI）]、有机和聚合物合成组[齐默尔曼，UI]以及生物成像和血管医学组[Misra，马约诊所]之间的广泛跨学科合作实施。这项拟议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，因为它不仅将为组装多功能药物载体创造一种创新策略，而且还将验证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.