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

项目概述：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。总生存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性淋巴结（LN）并获得阴性手术切缘;失败 这样做增加了局部肿瘤复发的可能性并增加了肿瘤负荷。不幸的是，外科医生 切除技术主要依赖于视觉提示和触觉信息。虽然重大进展 已取得实时术中荧光成像技术，有无针对性 可以特异性检测局部疾病或鉴定一种或多种分子的术中成像探针 识别癌症本身的特征。这突出了开发新的和临床可翻译的 高分辨率的术中可视化工具，可以特异性地定位淋巴结转移和残留 疾病沿着边缘，同时允许肿瘤的准确分子表征或表型。一个这样 下一代成像技术是一种超亮、直径小于8纳米的荧光核壳二氧化硅 纳米颗粒，康奈尔素数点（C'点），可以用PC靶向肽进行表面修饰，以准确地 鉴定一种或多种转移性标志物，包括PSMA。由于并非所有高风险PC都表达PSMA， 作为互补多路复用策略的一部分，这对于测定其他靶标如GRPr是重要的。因此 该提案的长期目标是创建基于荧光的PC靶向多路复用工具（Cornell prime 点，C'点），用于改善高风险PC患者中癌症靶点的术中检测。这样的 基于精确度的方法可用于对可能通过手术切除治愈的高风险PC患者进行分层 从那些需要系统治疗。这一战略也建立在我们之前成功的翻译和 临床试验的努力。作为我们之前R 01应用的扩展，我们完成了第一阶段的首次人体试验， 使用第一代FDA IND批准的整合素靶向治疗转移性黑色素瘤患者的PET成像试验 具有良好的“目标或清除”能力的粒子示踪剂。我们积极的术中临床试验利用了 这种高荧光粒子技术用于黑色素瘤患者淋巴结转移的图像引导治疗。 在本申请中，我们将使用含有Cy5.5的寡核苷酸靶向两种充分表征的PC标志物PSMA和GRPr。 本发明涉及含有PSMA和cw 800的靶向GRPr的C'点，根据以下目的： 用于近红外染料（NIR）包封PSMA和GRPr靶向C'点的表面化学， 体外生物学特性;（2）评估优化的杂合C'的肿瘤选择性摄取和药代动力学特征 （3）在表达PSMA和GRPr的模型中形成光谱不同的含NIR染料的C'点， 引导候选物允许准确和灵敏地同时检测在结上表达多个标记物 和远端转移;和（4）鉴定用于IND使能研究的主要PSMA靶向C' dot候选物， 早期临床试验，以评估可行性，粒子安全性，剂量测定和癌症检测能力。

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.