Highly Paramagnetic, Biodegradable Nanoclusters for Imaging Prostate Cancer

描述(申请人提供)：前列腺特异性抗原(PSA)筛查的广泛使用导致前列腺癌的更早发现和总死亡率的显著降低；然而，它也导致了对惰性疾病的过度诊断和过度治疗。PSA触发的活检通常是为了提高特异性，但由于大多数肿瘤的固有异质性，活检也被证明在前列腺癌的分期上不准确。我们假设分子成像策略提供了改善鉴别诊断和分期的机会，因为它能够提供关于疾病的位置、大小、范围和分级的更准确的信息。这项建议的总体目标是开发肿瘤靶向的Gd-偶联树枝状大分子纳米簇(DNCS)，作为一种超灵敏的T1磁共振(MR)成像对比剂，用于前列腺癌的特异性检测。DNCS将与抗体F77的单链抗体偶联，F77识别一种独特的糖脂抗原，该抗原在雄激素依赖和雄激素非依赖性前列腺癌细胞表面特异性表达。该建议的具体目标是(1)合成可生物降解的Gd结合的DNCs；(2)评估肿瘤靶向DNCs的毒性、特异性靶向能力和在培养中的摄取；以及(3)评估在前列腺癌原位小鼠模型中检测肿瘤的能力。这项建议的长期目标是开发一种造影剂，可以改善前列腺癌的鉴别诊断和分期，从而减少或消除疾病的过度治疗。

DESCRIPTION (provided by applicant): The widespread use of prostate-specific antigen (PSA) screening has led to earlier detection and a dramatic reduction in overall mortality of prostate cancer; however it has also resulted in over diagnosis and over treatment of indolent disease. PSA-triggered biopsies are generally performed to improve specificity, but biopsies have also proven to be inaccurate in the staging of prostate cancer because of the inherent heterogeneity of most tumors. We hypothesize that molecular imaging strategies offer an opportunity for improved differential diagnoses and staging, due to the ability to provide more accurate information on the location, size, extent, and grade of disease. The overall objective of this proposal is to develop tumor-targeted Gd-conjugated dendrimer nanoclusters (DNCs) as an ultra-sensitive T1 magnetic resonance (MR) imaging contrast agents for the specific detection of prostate cancer. DNCs will be conjugated to the scFv of antibody F77, which recognizes a unique glycolipid antigen that is specifically expressed on the cell surface of both androgen-dependent and androgen-independent prostate cancer cells. The specific aims for the proposal are (1) to synthesize biodegradable, Gd-conjugated DNCs; (2) evaluate the toxicity, specific targeting capabilities, and uptake of tumor-targeted DNCS in culture; and (3) evaluate the ability to detect tumors in orthotopic mouse models of prostate cancer. The long-term goal of this proposal is to develop a contrast agent that can provide improved differential diagnoses and staging of prostate cancer and thus reduce or eliminate the over-treatment of the disease.