Targeted Molecular Agents for Photoacoustic Imaging of Prostate Cancer

描述(由申请人提供)：这项提议的目的是通过使用光声成像(PAI)的新方法结合专门针对前列腺癌组织的新型近红外(NIR)成像剂来改变前列腺癌(PrCa)的筛查和诊断。靶向分子显像剂(TMIA)是基于外源近红外荧光(NIRF)和猝灭(NIRQ)染料，这两种染料将单独或联合使用来特异性靶向PrCa组织。这项技术建立在罗彻斯特理工学院(RIT)和罗切斯特大学医学中心(URMC)研究人员之间的一项新研究合作中，在PAI仪器和技术方面取得的最新进展，使用内源染料来处理PrCa的PAI。目前迫切需要为前列腺特异性抗原(PSA)筛查提供经济实惠的确认，可靠地指导穿刺针活检和监测PrCA的治疗。我们的策略结合了我们在RIT开发的新的合成方法，用于制备建立在多肽支架上的单模和双模显像剂，其特点是促进它们与包括抑制剂、多肽、抗体和适配子在内的生物分子的温和结合。在多肽支架的侧链上合成预先形成的NIRQ-NIRF染料对之后，将连接到两个不同的靶向前列腺特异性膜抗原(PSMA)催化部位的基序。这些靶向基序是：与小尿素YC-27相关的小分子抑制物；以及RNA适配子A10-3.2。膜抗原，前列腺特异性膜抗原(PSMA)，在几乎所有前列腺癌和相对较少的其他组织中表达，使其成为高度特异的靶点。 成像。此外，它已经成功地被用于其他PrCa成像应用，并被用作治疗靶点。因此，它代表了PrCa成像的良好靶点，对于NIRF-NIRQ方法来说是实现PAI成像的特异性、敏感性和增加成像深度的理想选择。使用含有NIRF染料的TMIA，通过体外共聚焦荧光显微镜(CFM)评估与PrCa细胞的结合效率，以确保靶向策略的稳健性。对PAI中TMIAs的体外评估将在URMC进行，在具备PrCa PAI体外模体应用专业知识的成像科学家的指导下进行。这项建议的关键是每年有四名本科生和一名研究生院的研究生参与，其中两人也将在市建局进行研究。这次合作突出了RIT的CFM在显像剂合成和评估方面的专业知识，以及URMC在癌症生物学和PAI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，目的是改变PrCa的筛查和诊断，并通过PAI指导活检：一种新的、可靠和廉价的成像方法。

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.