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对前列腺癌检测的改进 目标为PSMA 前列腺癌(PCA)活检通常使用超声(US)引导进行，但 前列腺内的肿瘤与美国不清楚。这导致目前的护理标准导致发病率上升。 不是针对特定目标而是针对可能发现癌症的典型位置的活组织检查。成象 肿瘤在腺体内和腺体周围间隙的位置将显著影响分期 这种疾病的危害。因此，开发一种准确描述前列腺癌的新工具是当务之急。 需要帮助进行分期和活检指导。为了满足这一需求，这项提议将形成有针对性的美国对比 药物，它可以外渗到前列腺癌细胞，并可以更有效地描绘关注的目标病变比 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。为明确识别PCA提供一个更好、更实用的工具 对于活检，我们已经开发了一种针对PSMA的纳米尺寸的US造影剂(称为纳米气泡-NB) 通过一种新的、高度特异的基于小分子的配体。靶向NBS在结构上与临床相似 用过的微泡(MB)，在临床US上清晰可见。与保留在血管系统中的MB相反， &lt；120 nm的Nb尺寸使它们能够渗出并直接结合到癌细胞上。这可能会导致更高的 肿瘤本身的对比度积累导致更好的分辨率和对PCA的检测。PSMA-目标 由于美国拥有如此广泛的可获得性、低成本和安全性，AGENT有能力彻底改变PCA成像。 重要的是，US已经被频繁地用于PCA活检术。这项研究的目的是 一种独特的增强检测和勾画前列腺癌的造影剂的研制及应用 两种互补策略：1)靶向NB后前列腺癌细胞表面PSMA的检测 2)监测肿瘤组织和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NBS可以直接靶向PCa细胞，因此将更有效地检测 与MBS相比，将前列腺癌描述为前列腺癌内和前列腺外的前列腺癌。我们提出了四个具体目标来支持 项目目标：目标1将确定国家BS的最佳配方参数。我们在寻找一个马厩 将以高产量成功地定向于PSMA的配方。配方需要在US上可见 并将其信号保持至少1小时，以便进行活检程序。泡沫将会是 用动态光散射、共聚焦显微镜和US进行了表征。体外结合效率和细胞摄取 将在细胞培养中进行筛选。AIM 2将最大化PSMA正侧和负侧的超声NB信号 并将其性能与临床上可用的MBS进行比较。目标3将检查性能 在临床相关的原位模型中。我们将获得对比度增强的图像，然后将利用 3D全鼠冷冻成像以确定分割肿瘤和前列腺组织的效果 直接比较通过超声成像确定的前列腺癌的组织学和位置。最后，在目标4中，我们将测试 前列腺癌犬模型的策略。我们希望以PSMA为目标的国家统计局将描绘出 前列腺腺内或腺外的原发肿瘤，并为活检和外科手术的计划提供信息。 PCA和US信号将在体内与狗的MRI进行关联，然后在体外使用 病理学。改进的活检和癌症定位将导致对高级别肿瘤的检测增加，并 肿瘤分期，发病率较低。