Polymer chelate conjugates for Diagnostic cancer imaging

描述(由申请人提供)： 这项研究的目标是开发安全、有效的靶向聚合物-格拉络合物作为磁共振诊断癌症成像的造影剂。癌症是美国人类死亡的主要原因之一。癌症早期的准确诊断和随后的最佳治疗对于挽救癌症患者的生命至关重要。磁共振成像(MRI)是一种非侵入性的临床诊断技术，但缺乏用于肿瘤早期发现和定性的功能性造影剂。新型靶向聚合物造影剂将提高MRI检测小癌和癌前组织的敏感性和准确性。本研究的具体目的是设计、合成和表征靶向和非靶向的L-谷氨酸-Gd(111)螯合物和单抗Fab‘片段靶向的聚(L-谷氨酸)-Gd(111)螯合物作为磁共振造影剂；评价靶向和非靶向结合物的分子质量分布、弛豫度、Gd螯合物释放、体内清除、生物分布、肿瘤靶向性、药代动力学和安全性；评价靶向和非靶向结合物对肿瘤磁共振成像对比剂增强的效果。生物相容的聚(L-谷氨酸)将被用作载体，Gd(III)DOTA将通过可切割的间隔体连接到聚合物上，该间隔体将很容易被切割，从聚合物中释放Gd螯合物，并在磁共振检查后促进其从体内清除。针对肿瘤组织中表达的分子标志物的单抗Fab‘片段将被掺入到聚合物结合物中，以实现肿瘤特异性MRI对比度增强。靶向造影剂将能够与分子靶标结合，并在靶组织中提供足够量的顺磁性螯合物，用于小肿瘤的成像。这些结合物的结构、物理化学和生物学特性将进一步优化，以开发安全、有效的造影剂，以便通过核磁共振进行更准确的癌症检测和分期。该项目的长期目标是开发安全、有效、功能性的造影剂，用于临床磁共振癌症成像。

DESCRIPTION (provided by applicant): The objectives of this research are to develop safe, effective targeted polymer-gadolinium chelate conjugates as contrast agents for magnetic resonance diagnostic cancer imaging. Cancer is one of the leading causes of human death in the United States. The accurate diagnosis and subsequent optimal treatment of cancer at its earliest stage is crucial to save the lives of cancer patients. Magnetic resonance imaging (MRI) is a non-invasive clinical diagnostic technique, but lacks of functional contrast agents for earlier tumor detection and characterization. The novel targeted polymeric contrast agents will increase the sensitivity and accuracy of the detection of small cancers and precancerous tissues with MRI. The specific aims are to design, synthesize and characterize poly(L-glutamic acid)-gadolinium (111) chelate conjugates and monoclonal antibody Fab' fragment targeted poly(L-glutamic acid)-Gd(lll) chelate conjugates as MRI contrast agents with minimal long-term Gd(lll) tissue accumulation; to evaluate the physicochemical and biological properties, including molecular weight distribution, relaxivity, Gd chelate release, in vivo clearance, biodistribution, neoplastic targeting, pharmacokinetics and safety, of the targeted and nontargeted conjugates; to assess the efficacy of the targeted and nontargeted conjugates on tumor contrast enhancement in MR imaging. The biocompatible poly(L-glutamic acid) will be used as a carrier and Gd(III)DOTA will be conjugated to the polymer via cleavable spacers, which will be readily cleaved to release the Gd chelate from the polymer and to facilitate its clearance from the body after the MRI exam. Monoclonal antibody Fab' fragments against the molecular markers expressed in neoplastic tissues will be incorporated into the polymer conjugates to achieve tumor specific contrast enhancement in MRI. The targeted contrast agents will be able to bind to the molecular targets and deliver a sufficient amount of paramagnetic chelates in target tissues for the imaging of small cancers. The structural, physicochemical and biological properties of the conjugates will be further optimized to develop safe, efficacious contrast agents for more accurate cancer detection and staging with MRI. The long-term goal of this project is to develop safe, effective, functional contrast agents for clinical MR cancer imaging.