Improved Detection of Prostate Cancer with Nanoparticle-based Ultrasound Contrast Agents Targeted to PSMA

使用针对 PSMA 的纳米颗粒超声造影剂改进前列腺癌的检测

基本信息

批准号：
10067372
负责人：
James Peter Basilion
金额：
$ 63.17万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10067372
关键词：
3-Dimensional Animal Model Antigen Targeting Binding Biodistribution Biological Biological Assay Biopsy Brachytherapy Canis familiaris Cell Culture Techniques Cells Cessation of life Clinical Confocal Microscopy Contrast Media Data Detection Development Diagnosis Diagnostic Neoplasm Staging Disease Drug Kinetics Equipment Extravasation FOLH1 gene Formulation Foundations Frequencies Gland Histologic Histology Hour Image Image Enhancement Imaging Techniques In Vitro Lesion Ligands Localized Malignant Neoplasm Location Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Measurement Measures Microbubbles Modeling Molecular Biology Molecular Target Monitor Morbidity - disease rate Mus Neoplasm Metastasis Operative Surgical Procedures PSA screening Pathology Patients Pattern Performance Phase 0/1 Clinical Trial Primary Neoplasm Procedures Process Prostate Prostatectomy Prostatic Neoplasms Reporting Research Resolution Screening for Prostate Cancer Signal Transduction Staging Structure Surface Surface of the Prostate Testing Therapeutic Tissues Treatment outcome Ultrasonography Work base biomarker development cancer cell cancer imaging cancer site clinical translation clinically relevant contrast enhanced cost digital experimental study imaging study improved in vivo light scattering men molecular marker nanobubble nanoparticle nanoscale nanosized novel marker optical imaging overexpression prostate cancer cell prostate cancer model rectal small molecule standard of care targeted agent tool tumor uptake

项目摘要

ABSTRACT Improved Detection of Prostate Cancer with New Nanoparticle-based Ultrasound Contrast Agents Targeted to PSMA Prostate cancer (PCa) biopsies are commonly performed using ultrasound (US) guidance, but the delineation of tumors within the prostate with US is not clear. This has led to rising morbidity from current standard of care biopsies that are not aimed at a specific target but rather typical locations where cancer may be found. Imaging of the location of the tumor within the gland and the peri-glandular space would significantly impact the staging of the disease. The development of a new tool to accurately depict cancer within the prostate is thus urgently needed to aid in staging and biopsy guidance. To meet this need, this proposal will develop targeted US contrast agents, which can extravasate to PCa cells and can delineate a target lesion of concern more effectively than current standard of care. Prostate specific membrane antigen (PSMA) is an ideal target to detect PCa due to its abundant expression in most prostate cancers. To provide a better, practical tool for clear identification of PCa for biopsy, we have developed a nano-sized US contrast agent (called a nanobubble – NB) targeted to PSMA via a new, highly specific small molecule-based ligand. The targeted NBs, are similar in structure to clinically used microbubbles (MB) and are clearly visible on clinical US. In contrast to MB which remain in the vasculature, the <120 nm NB size enables them extravasate and directly bind to cancer cells. This can result in higher accumulation of contrast at the tumor itself leading to better resolution and detection of PCa. The PSMA-targeted agent has the capacity to revolutionize PCa imaging, since US is so broadly available, low cost, and safe. Importantly, US is already frequently utilized in PCa biopsy procedures. The objective of this research is development of a uniquely capable contrast agent for enhanced detection and delineation of PCa with US using two complementary tactics: 1) detection of PSMA on the surface of prostate cancer cells after targeted NB extravasation and 2) monitoring differences in contrast agent dynamics in tumor versus normal prostate tissue. We hypothesize that PSMA-targeted NBs can target PCa cells directly and will thus be more effective at detecting and delineating PCa within and outside of the prostate gland than MBs. We propose four specific aims to support the project objectives: Aim 1 will determine the optimal formulation parameters for the NBs. We seek a stable formulation that will be successfully targeted to PSMA with high yield. The formulation needs to be visible on US and sustain its signal for at least 1 hour to allow for the biopsy procedure to take place. Bubbles will be characterized by dynamic light scattering, confocal microscopy and US. In vitro binding efficacy and cell uptake will be screened in cell culture. Aim 2 will maximize ultrasound NB signal in PSMA positive and negative flank tumors in mice and compare performance to MBs that are clinically available. Aim 3 will examine performance of the NBs in a clinically relevant orthotopic model. We will acquire contrast enhanced images and will then utilize 3D whole mouse cryoimaging to determine the efficacy of segmentation of the tumor and prostate tissue and directly compare histology and location of PCa determined using US imaging. Finally, in Aim 4, we will test the strategy in a dog model of prostate cancer. It is our hope that PSMA-targeted NBs will depict the pattern of primary tumor within or outside the prostate gland and inform planning for biopsy and surgical approaches. Correlation of Pca and US signal will be made in vivo with MRI of the dogs and then confirmed ex vivo using pathology. Improved biopsies and cancer localization will lead to increased detection of high grade tumors and tumor staging, and lower morbidity.

抽象的使用新型纳米颗粒超声造影剂改进前列腺癌的检测针对 PSMA 前列腺癌 (PCa) 活检通常使用超声 (US) 引导进行，但描绘前列腺内肿瘤与超声的关系尚不清楚，这导致当前护理标准的发病率上升。活检不是针对特定目标，而是针对可能发现癌症的典型位置。肿瘤在腺体内和腺周间隙的位置将显着影响分期因此，迫切需要开发一种能够准确描述前列腺癌的新工具。为了满足这一需求，该提案将开发有针对性的超声造影。药物，可以外渗到 PCa 细胞，并且可以比药物更有效地描绘出关注的目标病变目前的护理标准是，前列腺特异性膜抗原 (PSMA) 是检测 PCa 的理想靶点。在大多数前列腺癌中大量表达，为明确识别 PCa 提供更好、实用的工具。对于活检，我们开发了一种针对 PSMA 的纳米级 US 造影剂（称为纳米气泡 - NB）通过一种新的、高度特异性的小分子配体，靶向 NB 的结构与临床相似。使用微泡（MB）并且在临床超声上清晰可见，与保留在脉管系统中的MB相比， <120 nm 的 NB 尺寸使它们能够外渗并直接与癌细胞结合，这可能会导致更高的结果。肿瘤本身的对比积累可提高 PCa 的分辨率和检测效果。由于 US 的应用广泛、成本低廉且安全，因此该药物有能力彻底改变 PCa 成像。重要的是，美国已经在 PCa 活检过程中经常使用。这项研究的目的是。开发一种功能独特的造影剂，用于增强超声检查和勾画 PCa 两种互补的策略：1）靶向NB后检测前列腺癌细胞表面的PSMA 外渗；2) 监测肿瘤与正常前列腺组织中造影剂动力学的差异。我们追求 PSMA 靶向 NB 可以直接靶向 PCa 细胞，从而更有效地检测我们提出了四个支持的具体目标。项目目标：目标 1 将确定 NB 的最佳配方参数。能够以高产量成功靶向 PSMA 的制剂该制剂需要在美国可见。并维持其信号至少 1 小时，以便进行活检程序。通过动态光散射、共聚焦显微镜和超声来表征。将在细胞培养物中进行筛选，目标 2 将最大化 PSMA 正侧和负侧的超声 NB 信号。小鼠肿瘤并将性能与临床可用的 MB 进行比较，目标 3 将检查性能。我们将获取对比增强图像，然后利用临床相关原位模型中的 NB。 3D 全小鼠冷冻成像以确定肿瘤和前列腺组织的分割效果直接比较使用 US 成像确定的 PCa 的组织学和位置最后，在目标 4 中，我们将测试我们希望针对 PSMA 的 NB 能够描述前列腺癌的模式。前列腺内部或外部的原发性肿瘤，并为活检和手术方法的规划提供信息。 Pca 和 US 信号的相关性将通过狗的 MRI 在体内进行，然后使用体外确认改进的活检和癌症定位将导致高级别肿瘤和癌症的检测增加。肿瘤分期，并降低发病率。