Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging.

 描述(申请人提供)：前列腺癌早期检测和筛查的改进降低了癌症特有的死亡率，减少了晚期疾病并发症的人数，使患者受益。然而，前列腺癌的早期诊断与过度治疗的可能性之间的平衡仍然是一个临床难题。为了区分侵袭性和惰性疾病，我们提出了一种微创分子成像方法来检测不含整合素的Tetraspanin CD151。CD151是前列腺上皮细胞迁移开关所产生的CD151池。前列腺癌患者术后早期生化复发和转移的预测指标是无CD151水平升高。组织学分析表明，在前列腺癌中选择性地检测到无CD151的基因，而在健康的前列腺癌中则没有。我们的研究表明，CD151是一个独立的预后因素，与单独的Gleason分级和PSA水平相比，显著提高了预测价值。我们提出了一种非侵入性磁共振(MR)成像方法来检测和监测CD151的无表达以帮助前列腺癌的预后。为了获得足够的有效载荷传递和磁共振对比度增强，我们提出了一种分子靶向的大分子磁共振探针，这是我们最近开发的。该造影剂携带大量的螯合Gd(DOTA)，表现出~35,000 mm-1s-1的t1，比目前临床药物的t1高四个数量级。造影剂是利用烟草花叶病毒(TMV)形成的蛋白质基中空纳米管自组装而成的。纳米管的细长形状使其能够躲避单核吞噬细胞系统，并增强了分子靶标识别。肿瘤病变和转移灶中CD151的特异性靶向将通过与CD151结合的免疫结合物和具有高特异性和亲和力的多肽配体来实现。我们推测，无CD151靶向、形状优化、高MR信号增强的造影剂将敏感地显示原发灶和隐匿性转移灶中无CD151的表达。通过AIM 1，我们将开发一种不含CD151的双光磁共振探针。靶向、负载Gd(DOTA)的造影剂将被组装，靶标特异性将根据表面涂层(隐形涂层与伪装)和纳米颗粒形状进行评估。目的2将重点确定异种移植和转移小鼠模型中的体内磁共振成像参数；靶向MRI增强和CD151的无特异性将通过光学成像和组织学来验证。目的3评估我们的显像剂在纵向监测疾病进展和治疗反应方面的效用。将通过研究潜在的免疫反应、Gd的释放和清除以及组织毒性来评估造影剂的安全性。这种方法的成功将使前列腺癌分层和预后以及随访成为可能；数据表明，无CD151与其他人类恶性肿瘤的侵袭性相关，因此该方法可能在癌症预后中找到广泛的适用性。

 DESCRIPTION (provided by applicant): Improvements in early detection and screening for prostate cancer have benefited patients by reducing cancer- specific mortality and decreasing the number of those that suffer from the complications of advanced disease. Nevertheless, the balancing of early diagnosis with the potential for overtreatment of prostate cancer remains a clinical dilemma. To distinguish between aggressive and indolent disease, we propose a minimally invasive molecular imaging approach to detect integrin-free tetraspanin CD151free. CD151free is a pool of CD151 that arises as a result of a cell migration switch in prostate epithelium. Increased CD151free levels are predictive of early biochemical recurrence and metastasis in prostate cancer patients post-prostatectomy. Histology analysis indicates that CD151free is selectively detected in prostate cancer, and not in healthy prostate glands. Our studies indicate CD151free to be an independent prognostic factor, significantly improving predictive value compared to Gleason grading and PSA level alone. We propose a non-invasive magnetic resonance (MR) imaging approach to detect and monitor CD151free expression to aid prostate cancer prognosis. To achieve sufficient payload delivery and MR contrast enhancement, we propose a molecularly-targeted macromolecular MR probe that we recently developed. The contrast agent carries a large payload of chelated gadolinium Gd (DOTA) and exhibits a T1 of ~35,000 mM-1s-1, which is four orders of magnitude higher than the T1 of current clinical agents. The contrast agent is self-assembled using protein-based, hollow nanotubes formed by tobacco mosaic virus (TMV). The elongated shape of the nanotube enables evasion from the mononuclear phagocyte system and enhances molecular target recognition. Specific targeting to CD151free in cancerous lesions and metastatic sites will be achieved through immunoconjugates and peptide ligands that bind to CD151free with high specificity and affinity. We hypothesize that the CD151free-targeted, shape-optimized contrast agent with high MR signal enhancement will provide sensitive delineation of CD151free expression in primary lesions and occult metastases. Through Aim 1, we will develop a CD151free-specific dual optical-MR probe. Targeted, Gd (DOTA)-loaded contrast agents will be assembled, and target-specificity will be evaluated in dependence of surface coating (stealth coating vs. camouflage) and nanoparticle shape. Aim 2 will focus to determine the in vivo MR imaging parameters in xenograft and metastatic mouse models; targeted MRI enhancement and CD151free-specificity will be validated with optical imaging and histology. Aim 3 sets out to evaluate the utility of our imaging agent in monitoring disease progression and response to treatment longitudinally. Safety of the contrast agents will be evaluated by studying potential immune response, Gd-release and clearance, as well as tissue toxicity. Success in this approach would enable prostate cancer stratification and prognosis as well as follow-up; data indicate correlation of CD151free with aggressiveness of other human malignancies, and therefore this approach may find broad applicability in cancer prognosis.