Highly Paramagnetic, Biodegradable Nanoclusters for Imaging Prostate Cancer

描述（由申请人提供）：前列腺特异性抗原（PSA）筛查的广泛使用导致前列腺癌的早期检测和总体死亡率的显著降低;然而，它也导致了对惰性疾病的过度诊断和过度治疗。PSA触发的活检通常用于提高特异性，但由于大多数肿瘤的固有异质性，活检在前列腺癌分期中也被证明是不准确的。我们假设，分子影像学策略提供了一个机会，改善鉴别诊断和分期，由于能够提供更准确的信息的位置，大小，程度和疾病的等级。该提案的总体目标是开发肿瘤靶向Gd-缀合的树枝状聚合物纳米簇（DNC）作为用于前列腺癌特异性检测的超灵敏T1磁共振（MR）成像造影剂。DNC将与抗体F77的scFv缀合，所述抗体F77识别在雄激素依赖性和雄激素非依赖性前列腺癌细胞的细胞表面上特异性表达的独特糖脂抗原。该提案的具体目标是（1）合成可生物降解的Gd缀合的DNC;（2）评估毒性，特异性靶向能力和培养物中肿瘤靶向DNC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。这项提案的长期目标是开发一种造影剂，可以提供改进的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。 公共卫生相关性：该提案的总体目标是开发肿瘤靶向Gd-缀合的树枝状聚合物纳米簇（DNC）作为用于前列腺癌特异性检测的超灵敏T1磁共振（MR）成像造影剂。DNC将与抗体F77的scFv缀合，所述抗体F77识别在雄激素依赖性和雄激素非依赖性前列腺癌细胞的细胞表面上特异性表达的独特糖脂抗原。

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. PUBLIC HEALTH RELEVANCE: 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.