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

使用超小二氧化硅纳米粒子进行高风险前列腺癌手术治疗的分子表型分析和图像引导

• 批准号: 10908927
• 负责人: Michelle S Bradbury
• 金额: $ 43.11万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10908927
• 关键词: Acute; Affinity; Antigen Targeting; Automobile Driving; Beds; Binding; Biological; Biological Assay; Biological Markers; Bombesin Receptor; Cancer Detection; Cancer Etiology; Cancer Patient; Cancerous; Cell Line; Cessation of life; Chemicals; Chemistry; Clinical; Clinical Trials; Clinical Trials Design; Cues; Data; Detection; Development; Diameter; Disease; Distant Metastasis; Dose; Drug Kinetics; Dyes; Encapsulated; Ethics; Evaluation; Excision; FOLH1 gene; Failure; Feedback; Fluorescence; GRP gene; Generations; Goals; Histology; Human; Hybrids; Image-Guided Surgery; Imaging Techniques; Imaging technology; In Vitro; Individual; Integrins; Kinetics; LAPC4; LNCaP; Lead; Ligands; Localized Disease; Lymph Node Mapping; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Metastatic Melanoma; Metastatic Neoplasm to Lymph Nodes; Microscopic; Modality; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Neoplasm Metastasis; Nodal; Oncogenic; Operative Surgical Procedures; Optics; Organoids; Outcome; Patient-Focused Outcomes; Patients; Peptides; Phase; Phenotype; Positron-Emission Tomography; Pre-Clinical Model; Process; Property; Prostate; Radiolabeled; Radiometry; Recurrent tumor; Resected; Residual Neoplasm; Resolution; Rodent Model; Safety; Screening for Prostate Cancer; Silicon Dioxide; Specificity; Staging; Surface; Surgeon; Surgical Management; Surgical margins; Systemic Therapy; Tactile; Techniques; Therapeutic; Time; Tissues; Toxicology; Tracer; Translational trial; Translations; Tumor Burden; VCaP; Variant; Visual; Visualization; Visualization software; Work; Xenograft Model; cancer biomarkers; cancer heterogeneity; clinical candidate; clinical translation; cyanine dye 5; cytotoxicity; design; detection limit; detection sensitivity; disease heterogeneity; dosimetry; draining lymph node; early phase clinical trial; first-in-human; fluorescence imaging; high risk; human subject; image guided; imaging capabilities; imaging probe; imaging study; improved; in vivo; inhibitor; lead candidate; lymph nodes; melanoma; men; molecular imaging; molecular phenotype; nanoparticle; near infrared dye; next generation; optical imaging; overexpression; particle; patient stratification; pre-clinical; prostate cancer cell line; prostate cancer model; prostate cancer risk; prototype; safety study; safety testing; screening; targeted treatment; tool; tumor; uptake

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.

项目摘要：高风险前列腺癌（PC）是与癌症相关死亡的第二大最常见原因 在男人。总体生存和长期发病率的改善将取决于操作的能力 外科医生完全恢复区域转移性淋巴结（LNS）并获得阴性手术边缘；失败 为此，增加了局部肿瘤复发的可能性并增加了肿瘤伯嫩。不幸的是，手术 切除技术主要依赖于视觉提示和触觉信息。虽然取得了重大进展 已经在实时术中荧光成像技术中进行 术中成像问题可以特异性检测或鉴定一个或多个分子 定义癌症本身的签名。这突出了开发新的和临床翻译的重要性 高分辨率术中可视化工具，可以专门定位节点转移和残留 沿边缘的疾病，同时允许肿瘤的准确分子表征或表型。一个这样的 下一代成像技术是一种超右手，低于8 nm的直径荧光芯壳二氧化硅 纳米颗粒，康奈尔素点（C’Indots），可以用PC靶向肽进行表面修饰，以准确 识别包括PSMA在内的一个或多个转移标记。由于并非所有高风险PC表达PSMA，所以 重要的是，将其他目标（例如GRPR）作为完整的多路复用策略的一部分。因此， 该建议的长期目标是创建基于PC的荧光荧光多路复用工具（Cornell Prime） DOTS，C’DOTS）用于改善高风险PC患者癌症术中的术中检测。这样的 基于精确的方法可用于分层高危PC患者，可以通过手术切除来治愈 从需要全身治疗的人那里。该策略还基于我们先前的成功翻译和 临床试验。作为我们以前的R01应用程序的扩展，我们完成了第1阶段，第一个人类 使用第一代FDA批准的整联蛋白靶向转移性黑色素瘤患者的宠物成像试验 具有良好“目标或清除”功能的粒子示踪剂。我们主动术中临床试验已利用 这种高荧光的粒子技术，用于对黑色素瘤患者的淋巴结转移的图像引导治疗。 在此应用程序中，我们将使用含Cy5.5 根据以下目的：（1）可调 近红外染料（NIR）包含的PSMA-和GRPR靶向的C'DOTS的表面化学成分以优化 体外生物学特性； （2）评估优化杂种C'的肿瘤选择性摄取和药代动力学特征 PSMA和GRPR表达模型中的点； （3）从中发展出频谱赋予NIR染料的c'Dots 铅候选人允许对在节点上表达的多个标记的准确和敏感的并发检测 和遥远的转移； （4）确定用于指定研究的铅PSMA靶向C'DOT候选者 一项早期临床试验，以评估可行性，颗粒安全性，剂量法和癌症检测能力。