Targeted Molecular Agents for Photoacoustic Imaging of Prostate Cancer

用于前列腺癌光声成像的靶向分子制剂

• 批准号: 8811634
• 负责人: Hans F. Schmitthenner
• 金额: $ 44.44万
• 依托单位: ROCHESTER INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811634
• 关键词: Active Sites; Affinity; Algorithms; Amino Acids; Antigen Targeting; Antigens; Binding; Biology; Biopsy; Biotechnology; Cancer Biology; Catalytic Domain; Cell Culture Techniques; Cells; Chemistry; Collaborations; Confocal Microscopy; Contrast Media; Coupled; Diagnosis; Disease Progression; Dyes; Early Diagnosis; Ensure; Environment; Evaluation; Fluorescence; Fluorescence Microscopy; Fluorescence Spectroscopy; Fluorescent Dyes; Generations; Glutamate Carboxypeptidase II; Goals; Hemoglobin; High Pressure Liquid Chromatography; Housing; Image; Imaging Device; In Vitro; Institutes; Lasers; Lead; Learning; Malignant neoplasm of prostate; Measurement; Medical center; Membrane; Methodology; Methods; Modeling; Molecular Target; Monitor; Mus; Needle biopsy procedure; Oxyhemoglobin; Pain; Patients; Peptide antibodies; Peptides; Postdoctoral Fellow; Primary Health Care; Prostate; Prostate Cancer therapy; Prostate specific antigen measurement; Prostate-Specific Antigen; Protocols documentation; RNA; Relative (related person); Reporting; Research; Research Personnel; Science; Scientist; Screening for cancer; Sensitivity and Specificity; Serum; Side; Signal Transduction; Site; Specificity; Spectrum Analysis; Staining method; Stains; Students; Techniques; Technology; Testing; Tissue Model; Tissues; Ultrasonography; Universities; Urea; analog; aptamer; base; cancer imaging; cancer therapy; chromophore; data acquisition; deoxyhemoglobin; design; graduate student; imaging modality; inhibitor/antagonist; instrument; instrumentation; molecular imaging; novel; phantom model; photoacoustic imaging; polyproline; prostate cancer cell; public health relevance; scaffold; screening; small molecule; undergraduate student

DESCRIPTION (provided by applicant): The purpose of this proposal is to transform screening and diagnosis for prostate cancer (PrCa) by using new methods for photoacoustic imaging (PAI) coupled with novel near infrared (NIR) imaging agents that specifically target PrCa tissue. The targeted molecular imaging agents (TMIAs) are based on exogenous NIR fluorescent (NIRF) and quencher (NIRQ) dyes which will be used singly and in combination to specifically target PrCa tissue. The technology builds on recent advances made in PAI instrumentation and techniques using endogenous dyes for the PAI of PrCa in a new research collaboration between researchers at the Rochester Institute of Technology (RIT) and the University of Rochester Medical Center (URMC). There is a significant need to affordably provide confirmation for PSA (prostate specific antigen) screening, reliably guide needle biopsies and monitor therapy for PrCa. Our strategy incorporates new synthetic methods which we have developed at RIT for preparing single and dual modal imaging agents built on a peptide scaffold with features that facilitate their gentle conjugation to biomolecules including inhibitor, peptides, antibodies and aptamers. The synthesis of pre-formed NIRQ-NIRF dye pairs on the side chains of the peptide scaffold will be followed by conjugation to two different targeting motifs for the catalytic site of prostate specific membrane antigen (PSMA). These targeting motifs are: a small molecule inhibitor related to the small urea YC-27; and an RNA aptamer, A10-3.2. The membrane antigen, prostate specific membrane antigen (PSMA), is expressed on almost all prostate cancers and relatively few other tissues making it a highly specific target for imaging. Moreover it has already been successfully targeted in other PrCa imaging applications and used as a therapy target. Thus, it represents a well- established target for PrCa imaging that is ideal for the NIRF-NIRQ approach to enable specificity, sensitivity and increase depth of imaging by PAI. The binding efficacy to PrCa cells will be evaluated by in-vitro confocal fluorescence microscopy (CFM) using TMIAs containing NIRF dyes to ensure robustness of the targeting strategy. In-vitro evaluation of TMIAs in PAI will be performed at URMC under the guidance of imaging scientists with expertise in the application of in-vitro phantoms for PAI of PrCa. Key to this proposal is the involvement of four undergraduates and one graduate student from RIT in each year, two of whom will also conduct research at URMC. The collaboration highlights expertise in imaging agent synthesis and evaluation by CFM at RIT and the expertise in cancer biology and PAI at URMC. These provide a vibrant learning environment in cancer imaging research for undergraduates with the achievable goal of transforming screening and diagnosis of PrCa, and directing biopsies by PAI: a new, reliable and inexpensive imaging method.

描述（由申请人提供）：本提案的目的是通过使用光声成像（派）的新方法结合特异性靶向PrCa组织的新型近红外（NIR）成像剂来改变前列腺癌（PrCa）的筛查和诊断。靶向分子成像剂（TMIA）基于外源性NIR荧光（NIRF）和猝灭剂（NIRQ）染料，可单独使用或组合使用，以特异性靶向PrCa组织。该技术建立在派仪器和技术的最新进展的基础上，这些技术使用内源性染料用于PrCa的派，这是罗切斯特理工学院（RIT）和罗切斯特大学医学中心（URMC）的研究人员之间的一项新研究合作。非常需要提供PSA（前列腺特异性抗原）筛查的确认，可靠地引导针活检和监测PrCa治疗。我们的策略结合了我们在RIT开发的新的合成方法，用于制备构建在肽支架上的单模态和双模态成像剂，其特征在于促进其与生物分子（包括抑制剂、肽、抗体和适体）的温和缀合。在肽支架的侧链上合成预形成的NIRQ-NIRF染料对之后，将缀合至前列腺特异性膜抗原（PSMA）的催化位点的两个不同靶向基序。这些靶向基序是：与小脲YC-27相关的小分子抑制剂;和RNA适体A10-3.2。膜抗原，前列腺特异性膜抗原（PSMA），在几乎所有的前列腺癌和相对较少的其他组织上表达，使其成为前列腺癌的高度特异性靶标。 显像此外，它已经在其他PrCa成像应用中成功靶向并用作治疗靶点。因此，它代表了PrCa成像的良好确立的靶标，其对于NIRF-NIRQ方法是理想的，以实现特异性、灵敏度和增加派成像的深度。将使用含有NIRF染料的TMIA通过体外共聚焦荧光显微镜（CFM）评价与PrCa细胞的结合效力，以确保靶向策略的稳健性。将在具有PrCa派体外模型应用专业知识的成像科学家的指导下，在URMC进行派中TMIA的体外评价。这项提案的关键是每年有四名RIT的本科生和一名研究生参与，其中两人还将在URMC进行研究。该合作突出了RIT的CFM在成像剂合成和评估方面的专业知识以及URMC在癌症生物学和派方面的专业知识。这些为本科生提供了一个充满活力的癌症成像研究学习环境，其可实现的目标是改变PrCa的筛查和诊断，并通过派指导活检：一种新的，可靠的和廉价的成像方法。