Tumor-Targeted Paramagnetic Porous Polymersomes

描述(由申请人提供)：造影剂通常用于诊断磁共振成像，以帮助检测和表征病理异常。事实上，据估计，近50%的磁共振检查涉及使用磁共振造影剂。大多数临床上相关的基于Gd的药物是小的、非靶向的化合物，被动地分布到血管内和间质空间。然而，最近人们对顺磁性造影剂的开发产生了兴趣，这种造影剂能够通过配基靶向、酶活性和多重作用来探测组织的分子轮廓。可以预见，这些试剂可以用于获得更具体的临床诊断，从而改善患者管理。这项提议的总体目标是开发基于Gd包裹的多孔囊泡的分子靶向顺磁造影剂，用于体内肿瘤成像。我们磁共振成像平台的主要特点是：a)由两亲性两嵌段共聚物自组装形成的多孔纳米微囊；b)包裹在纳米微囊管腔内的高Gd有效载荷，导致高T1驰豫率(每个粒子)；以及c)肿瘤靶向配体结合到顺磁性纳米微囊上，用于将造影剂定位到感兴趣的部位。该方案的具体目的是(1)合成具有不同物理和磁性的Gd包裹的多孔囊泡；(2)表征抗HER2结合的顺磁囊泡在乳腺癌细胞中的结合和摄取；(3)评估肿瘤移植瘤的MR对比度增强。这项提议的长期目标将是进一步将顺磁性多孔性聚合体开发成治疗药物(即结合药物输送和成像)。然后，磁共振成像可以用来评估生物分布和治疗效果，这可以影响剂量和治疗方案的决定。当用作药物载体时，聚合体的疏水结构域为疏水药物提供了一个天然的载体环境，亲水化合物可以被负载到纳米微囊的水腔中。 与公共卫生相关：这项提案的总体目标是开发分子靶向的顺磁造影剂，该造影剂基于包裹Gd的多孔性聚合物囊泡。顺磁性多孔囊泡将被抗HER2/neu亲和抗体功能化，并将用于体外和体内特异性检测乳腺癌细胞。

DESCRIPTION (provided by applicant): Contrast agents are commonly used in diagnostic magnetic resonance (MR) imaging to help detect and characterize pathological abnormalities. In fact, it has been estimated that nearly 50 % of all MR examinations involve the use of MR contrast agents. Most clinically relevant Gd-based agents are small, non-targeted compounds that passively distribute into the intravascular and interstitial space. However, there has recently been emerging interest in the development of paramagnetic contrast agents that are capable of probing the molecular profile of tissues via ligand targeting, enzymatic activity and multiplexing. It is envisioned that these agents could be used to acquire a more specific clinical diagnosis and thus improve patient management. The overall goal of this proposal is to develop molecular targeted paramagnetic contrast agents based on Gd- encapsulated porous vesicles for in-vivo tumor imaging. The key features of our MR imaging platform are: a) porous nanovesicles formed from the self assembly of amphiphilic diblock copolymers; b) high Gd payloads encapsulated within the nanovesicle lumen, resulting in a high T1 relaxivity (per particle); and c) tumor- targeting ligands conjugated onto paramagnetic nanovesicles, which serve to localize the contrast agent to the site of interest. The specific aims for this proposal are (1) to synthesize Gd-encapsulated porous vesicles with various physical and magnetic properties; (2) characterize binding and uptake of anti-HER2-affibody conjugated paramagnetic vesicles in breast cancer cells; and (3) evaluate the MR contrast enhancement in tumor xenografts. The long-term goal of this proposal will be to further develop paramagnetic porous polymersomes into theranostic agents (i.e. combined drug delivery and imaging). MR imaging can then be used to assess biodistribution and therapeutic efficacy, which can impact decisions on dosing and treatment options. When used as a drug delivery vehicle, the hydrophobic domain of polymersomes provides a natural carrier environment for hydrophobic drugs and hydrophilic compounds can be loaded in the aqueous lumen of the nanovesicles. PUBLIC HEALTH RELEVANCE: The overall goal of this proposal is to develop molecular targeted paramagnetic contrast agents based on gadolinium-encapsulated porous polymer vesicles. The paramagnetic porous vesicles will be functionalized with anti-HER2/neu-affibodies and will be used to specifically detect breast cancer cells in vitro and in vivo.