Tumor-Targeted Paramagnetic Porous Polymersomes

描述（由申请人提供）：造影剂通常用于诊断性磁共振（MR）成像，以帮助检测和表征病理异常。事实上，据估计，近50%的MR检查涉及MR造影剂的使用。大多数临床相关的Gd基药物是小的、非靶向的化合物，其被动地分布到血管内和间质空间中。然而，最近出现的兴趣，顺磁性造影剂的发展，能够探测组织的分子概况通过配体靶向，酶活性和多路复用。据设想，这些药物可用于获得更具体的临床诊断，从而改善患者管理。本提案的总体目标是开发基于Gd封装的多孔囊泡的分子靶向顺磁性造影剂，用于体内肿瘤成像。我们的MR成像平台的关键特征是：a）由两亲性二嵌段共聚物的自组装形成的多孔纳米囊泡; B）封装在纳米囊泡腔内的高Gd有效载荷，导致高T1弛豫率（每个颗粒）;和c）缀合到顺磁性纳米囊泡上的肿瘤靶向配体，其用于将造影剂定位到感兴趣的部位。该提案的具体目的是（1）合成具有各种物理和磁性的Gd包封多孔囊泡;（2）表征乳腺癌细胞中抗HER 2抗体缀合的顺磁性囊泡的结合和摄取;以及（3）评价肿瘤异种移植物中的MR对比增强。该提案的长期目标将是进一步将顺磁性多孔聚合物囊泡开发成治疗诊断剂（即组合药物递送和成像）。然后，MR成像可用于评估生物分布和治疗效果，这可能会影响给药和治疗方案的决定。当用作药物递送载体时，聚合物囊泡的疏水结构域为疏水性药物提供天然载体环境，并且亲水性化合物可以装载在纳米囊泡的水性腔中。 公共卫生相关性：本提案的总体目标是开发基于钆包封的多孔聚合物囊泡的分子靶向顺磁性造影剂。顺磁性多孔囊泡将用抗HER 2/neu-bodies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.