BIOMEDICAL (BASIC)

用于前列腺癌的检测、分期和监测的分子靶向成像剂是 迫切需要。前列腺膜特异性抗原（PSMA）是一种膜糖蛋白， 前列腺癌，并且是基于抗体的成像剂ProstaScint的靶点。然而，ProstaScint 没有实现其作为临床或商业成像剂的承诺。我们建议使用蛋白质 工程化以产生基于人源化PSMA特异性的纳米级生物靶向试剂， 抗体的工程“微型抗体”（~ 8-10 nm）是抗体的一半大小，但保留完整的二价结合 并能够在体内快速定位和成像。技术目标是：1） 产生PSMA特异性微抗体; 2）用残基化（放射性金属螯合物）放射性标记生物分子 和非残留（放射性碘）标记; 3）评价体外细胞结合和内化;和4）进行 在携带前列腺癌异种移植物的小鼠中的microPET成像研究。这些技术的建立 将为产生具有任何特异性的显像剂创造一条途径。公共卫生相关性：研究 将产生一种新的成像剂，用于特异性检测患者的前列腺癌， 商业化这些PSMA特异性微抗体的成功将为以下方面奠定重要基础： 将这类生物分子用于另外的体内纳米靶向策略。

Molecularly targeted imaging agents for the detection, staging, and monitoring of prostate cancer are urgently needed. Prostate Membrane Specific Antigen (PSMA) is a membrane glycoprotein expressed by all prostate cancers, and is the target of the antibody-based imaging agent ProstaScint. However, ProstaScint has not fulfilled its promise as a clinical or commercial imaging agent. We propose to employ protein engineering to produce a nanoscale biological targeting reagent based on a humanized PSMA-specific antibody. Engineered "minibodies" ( ~ 8-10 nm) are half the size of antibodies, yet retain full bivalent binding to their target, and are capable of rapid localization and imaging in vivo. Technical objectives are to: 1) produce PSMA-specific minibodies; 2) radiolabel the biomolecules with residualizing (radiometal chelate) and non-residualizing (radioiodine) labels; 3) evaluate cell binding and internalization in vitro; and 4) conduct microPET imaging studies in prostate cancer xenograft-bearing mice. Establishment of these technologies will create a pathway for generating imaging agents with any specificity. Public health relevance: studies will produce a novel imaging agent for specific detection of prostate cancer in patients with goal of commercialization. Success of these PSMA-specific minibodies will establish important groundwork for using thi s class of biological molecules for additional in vivo nanotargeting strategies.