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

• 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
• 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

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.

摘要 新型纳米超声造影剂改善前列腺癌的检测 针对PSMA 前列腺癌（PCa）活检通常使用超声（US）引导进行，但前列腺癌（PCa）活检的描绘 前列腺内的肿瘤与超声不清楚。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。成像 肿瘤在腺体内和腺体周围间隙的位置对分期有显著影响 疾病。因此，迫切需要开发一种新的工具来准确描述前列腺内的癌症。 需要帮助分期和活检指导。为满足这一需求，这一提议将制定针对性的美国对比 药物，其可以外渗到PCa细胞，并且可以比常规药物更有效地描绘关注的靶病变。 目前的护理标准。前列腺特异性膜抗原（PSMA）是检测前列腺癌的理想靶点， 在大多数前列腺癌中大量表达。为PCa的明确识别提供更好、更实用的工具 对于活检，我们开发了一种针对PSMA的纳米级超声造影剂（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在结构上与临床上相似 使用微泡（MB），在临床US上清晰可见。与保留在脉管系统中的MB相反， <120 nm NB尺寸使它们能够外渗并直接结合癌细胞。这可能导致更高的 在肿瘤本身处的对比度的积累导致更好的分辨率和PCa的检测。靶向psma的 由于US是如此广泛可用、低成本和安全，因此该试剂具有革新PCa成像的能力。 重要的是，超声已经经常用于PCa活检程序。本研究的目的是 开发一种独特的造影剂，用于使用US增强PCa的检测和描绘 两种互补策略：1）在靶向NB后检测前列腺癌细胞表面上的PSMA 外渗和2）监测肿瘤与正常前列腺组织中造影剂动力学的差异。 我们假设PSMA靶向的NB可以直接靶向PCa细胞，因此在检测PCa细胞方面更有效。 并且描绘前列腺内和前列腺外的PCa而不是MB。我们提出了四个具体目标，以支持 项目目标：目标1将确定NB的最佳配方参数。我们在寻找一个稳定的 该制剂将以高产率成功靶向PSMA。制剂需在US上可见 并将其信号维持至少1小时以允许进行活组织检查程序。泡沫将是 通过动态光散射、共聚焦显微镜和US表征。体外结合效力和细胞摄取 将在细胞培养中筛选。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将审查业绩 临床相关原位模型中的NB。我们将获取对比度增强图像，然后利用 3D全小鼠冷冻成像，以确定肿瘤和前列腺组织分割的功效， 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 在前列腺癌的狗模型的策略。我们希望PSMA靶向的NB将描绘 前列腺内或外的原发性肿瘤，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犬的MRI在体内进行，然后使用 病理改进的活检和癌症定位将导致高级别肿瘤的检测增加， 肿瘤分期和低发病率。