Polymer chelate conjugates for Diagnostic cancer imaging

描述（由申请人提供）： 本研究的目的是开发安全、有效的靶向聚合物钆螯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。在癌症的早期阶段进行准确的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，但缺乏功能性造影剂的早期肿瘤检测和定性。新型靶向聚合物造影剂将提高MRI检测小肿瘤和癌前组织的灵敏度和准确性。具体目标是设计、合成和表征聚（L-谷氨酸）-钆（111）螯合物缀合物和单克隆抗体Fab'片段靶向的聚（L-谷氨酸）-Gd（III）螯合物缀合物作为MRI造影剂，具有最小的长期Gd（III）组织累积;评价其理化和生物学性质，包括分子量分布、弛豫率、Gd螯合物释放、体内清除率，靶向和非靶向缀合物的生物分布、肿瘤靶向、药代动力学和安全性;评估靶向和非靶向缀合物对MR成像中肿瘤对比增强的功效。生物相容性聚乙烯（L-谷氨酸）将被用作载体，Gd（III）DOTA将通过可裂解的间隔物与聚合物缀合，其将容易地被切割以从聚合物释放Gd螯合物并促进其在MRI检查后从体内清除。针对肿瘤组织中表达的分子标记物的单克隆抗体Fab'片段将被掺入聚合物缀合物中以实现肿瘤标记物的免疫治疗。MRI中特异性对比增强。靶向造影剂将能够结合分子靶标并在靶组织中递送足够量的顺磁性螯合物以用于小癌症的成像。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，用于更准确的癌症检测和MRI分期。本项目的长期目标是开发安全、有效、功能性的对比剂用于临床MR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.