Targeted Molecular Agents for Photoacoustic Imaging of Prostate Cancer

描述（由申请人提供）：本提案的目的是通过使用光声成像（PAI）的新方法以及特异性靶向PrCa组织的新型近红外（NIR）显像剂来改变前列腺癌（PrCa）的筛查和诊断。靶向分子显像剂（tmia）基于外源性近红外荧光（NIRF）和猝灭（NIRQ）染料，它们将单独或联合使用以特异性靶向PrCa组织。这项技术是在罗切斯特理工学院（RIT）和罗切斯特大学医学中心（URMC）的研究人员进行的一项新的研究合作中，基于PAI仪器和使用内源性染料进行PrCa PAI的技术的最新进展。有必要为PSA（前列腺特异性抗原）筛查提供负担得起的确认，可靠地指导针活检和监测PrCa治疗。我们的策略结合了我们在RIT开发的新的合成方法，用于制备建立在肽支架上的单模态和双模态显像剂，其特征有助于它们与生物分子（包括抑制剂、肽、抗体和适体）的温和结合。在肽支架侧链上合成预形成的NIRQ-NIRF染料对，然后结合前列腺特异性膜抗原（PSMA）催化位点的两个不同靶向基序。这些靶向基序是：与小尿素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），几乎在所有前列腺癌和相对较少的其他组织中表达，使其成为高度特异性的靶点

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.