Molecular Phenotyping and Image-Guidance for Surgical Treatment of High-Risk Prostate Cancer Using Ultrasmall Silica Nanoparticles

项目摘要：高危前列腺癌(PC)是癌症相关死亡的第二大常见原因 在男人身上。总体存活率和长期发病率的改善将取决于手术的能力 外科医生完全切除区域转移淋巴结(LNS)并获得阴性手术切缘；失败 这样做会增加局部肿瘤复发的可能性，并增加肿瘤负担。不幸的是，外科手术 切除技术主要依赖于视觉提示和触觉信息。在取得重大进展的同时 已有的术中实时荧光成像技术，尚无针对性 术中成像探头，可以特异性地检测局部疾病或识别一个或多个分子 定义癌症本身的签名。这突显了开发新的临床可翻译的重要性 高分辨率的术中可视化工具，可以特异性地定位结节转移和残留 肿瘤边缘的疾病，同时允许准确的分子特征或肿瘤的表型。这样的一个 下一代成像技术是一种超明亮的、直径小于8 nm的荧光核壳二氧化硅 纳米颗粒，康奈尔质点(C‘点)，可以用PC靶向多肽进行表面修饰，以获得准确的 确定一个或多个转移标志物，包括PSMA。由于并非所有高风险PC都支持PSMA，因此它是 重要的是分析其他目标，如GRPR，作为互补多路复用战略的一部分。因此，a 该提议的长期目标是创建基于PC的基于荧光的多路复用工具(康奈尔大学素数 DOTS，C‘DOTS)，用于改进高危PC患者术中癌症靶点的检测。这样的一个 基于精确度的方法可用于对可能通过手术切除治愈的高危PC患者进行分层 远离那些需要系统治疗的人。这一战略还建立在我们之前成功的翻译和 临床试验的努力。作为上一个R01应用程序的扩展，我们完成了第一阶段，这是人类中的第一个 FDA IND批准的第一代整合素靶向在转移性黑色素瘤患者中的PET成像试验 具有良好的“目标性或清晰性”能力的粒子示踪剂。我们积极的术中临床试验已经利用了 这项高荧光粒子技术用于图像引导治疗黑色素瘤患者的结节转移。 在本应用程序中，我们将使用包含Cy5.5的两个特性良好的PC标记PSMA和GRPR作为目标 根据以下目的：(1)确定可调谐的 近红外染料(NIR)包裹的PSMA和GRPR靶向C‘点的表面化学优化 体外生物学特性；(2)评价优化的杂交种C‘’的肿瘤选择性摄取和药代动力学 PSMA和GRPR表达模型中的点；(3)开发光谱明显的含有C‘的近红外染料点 引导候选对象允许准确、灵敏地同时检测节点上表达的多个标记 和远处转移；以及(4)确定靶向C‘点的先导PSMA以进行IND使能研究和 一项评估可行性、颗粒安全性、剂量学和癌症检测能力的早期临床试验。

Project Summary: High-risk prostate cancer (PC) is the second most common cause of cancer-related death in men. Improvements in overall survival and long-term morbidity will depend on the ability of the operating surgeon to completely resect regional metastatic lymph nodes (LNs) and obtain negative surgical margins; failure to do so increases the likelihood of local tumor recurrence and added tumor burden. Unfortunately, surgical resection techniques have principally relied upon visual cues and tactile information. While significant advances have been made in real-time intraoperative fluorescence imaging techniques, there are no targeted intraoperative imaging probes that can specifically detect local disease or identify one or more molecular signatures defining the cancer itself. This highlights the importance of developing new and clinically translatable high-resolution intraoperative visualization tools that can specifically localize nodal metastases and residual disease along margins, while permitting accurate molecular characterization or phenotyping of tumor. One such next-generation imaging technology is an ultrabright, sub-8-nm diameter fluorescent core-shell silica nanoparticle, Cornell prime dots (C’ dots), that can be surface-modified with PC-targeting peptides for accurately identifying one or more metastatic markers, including PSMA. Since not all high-risk PCs express PSMA, it is important to assay other targets, such as GRPr, as part of a complementary multiplexing strategy. Therefore, a long-term goal of this proposal is to create PC-targeting fluorescence-based multiplexing tools (Cornell prime dots, C’ dots) for improving the intraoperative detection of cancer targets in high-risk PC patients. Such a precision-based approach can be used to stratify high-risk PC patients potentially curable by surgical resection from those requiring systemic therapy. This strategy also builds upon our prior successful translational and clinical trial efforts. As an extension of our previous R01 application, we completed a Phase 1, first-in-human PET imaging trial in metastatic melanoma patients using a first-generation FDA IND-approved integrin-targeting particle tracer with favorable “target-or-clear” capabilities. Our active intraoperative clinical trials have exploited this highly-fluorescent particle technology for image-guided treatment of nodal metastases in melanoma patients. In this application, we will target two well-characterized PC markers, PSMA and GRPr, using Cy5.5-containing PSMA- and cw800-containing GRPr-targeting C’ dots, according to the following aims: (1) determine tunable surface chemistries for near-infrared dye (NIR)-encapsulated PSMA- and GRPr-targeted C' dots to optimize in vitro biological properties; (2) assess tumor-selective uptake and pharmacokinetic profiles of optimized hybrid C’ dots in PSMA- and GRPr-expressing models; (3) develop spectrally-distinct NIR dye-containing C’ dots from lead candidates to permit accurate and sensitive concurrent detection of multiple markers expressed on nodal and distant metastases; and (4) identify a lead PSMA-targeting C’ dot candidate for IND-enabling studies and an early-phase clinical trial to assess feasibility, particle safety, dosimetry, and cancer-detection capabilities.