(PQC-5) Zwitterionic NIR/Zr-89 Agents for Prostate Cancer Staging and Treatment

(PQC-5) 用于前列腺癌分期和治疗的两性离子 NIR/Zr-89 试剂

基本信息

批准号：
8687138
负责人：
John V Frangioni
金额：
$ 108.2万
依托单位：
CURADEL, LLC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-25 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8687138
关键词：
Affinity Animal Model Animals Applications Grants Area Attention Binding Biodistribution Biological Assay Biological Models Blood Budgets Cells Charge Chemical Structure Chemicals Contrast Media Cyclic GMP Deferoxamine Detection Diagnostic Neoplasm Staging Disease Dose Endocytosis Engineering Ensure Equilibrium Excision Exhibits Extracapsular Fluorescence Glutamate Carboxypeptidase II Goals Half-Life Human Image Indolent International Investigational Drugs Investigational New Drug Application Isotopes Kidney Label Left Ligands Light Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of prostate Maximum Tolerated Dose Membrane Neoplasm Metastasis Normal tissue morphology Nude Mice Operative Surgical Procedures Optics Organ PET/CT scan Patient Care Performance Pharmacologic Substance Phase Positron-Emission Tomography Procedures Process Property Prostate Prostatectomy Proteins Radiolabeled Renal clearance function Research Infrastructure Scanning Staging Structure Surgeon Synthesis Chemistry System Technology Testing Time Tissues Toxicology Validation base bone imaging cancer care cancer cell cancer imaging cancer therapy chelation cohort fluorophore functional group genotoxicity improved in vivo male mathematical model member men microbial alkaline proteinase inhibitor molecular imaging mouse model nanoparticle optical imaging prostate surgery public health relevance radiotracer receptor scale up small molecule tumor volunteer

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer presents a conundrum. On one hand, the vast majority of tumors are biologically indolent, and likely do not require treatment. On the other hand, tumors found to be locally advanced during surgery require aggressive treatment for cure. Even with this conundrum, molecular imaging has the potential to make an enormous impact on patient care. For staging, PET/MRI could identify tumors that are no longer organ-confined, and thus spare men from futile surgery. For men who are surgical candidates, optical imaging via near-infrared (NIR) fluorescence could provide real-time guidance during prostate resection, and importantly, highlight areas of extracapsular extension or in-transit metastases. To achieve both goals, though, a technology that improves cancer cell detection by at least 100-fold over conventional means is required. The hypothesis guiding this study is that zwitterionic contrast agents and radiotracers, defined as molecules with electrically-neutral and geometrically-balanced alternating positive and negative charges, will provide log-level improvements in molecular imaging. This hypothesis is based on observations from our group using small molecule, protein, and nanoparticle systems. In each case, zwitterionic molecules exhibited extremely low non-specific binding to normal tissues and organs. And, when engineered to exhibit rapid, renal- only clearance, unbound dose was eliminated completely from the body, resulting in high SBR. The focus of our study is prostate-specific membrane antigen (PSMA), a type II membrane receptor to which we have previously developed high affinity (2 and 9 nM) small molecule targeting ligands called GPI. We will create zwitterionic versions of GPI that have both optical (800 nm NIR fluorescence) and PET (deferoxamine chelation of Zr-89) functional groups (ZWGPI). Mathematical modeling of ZWGPI's performance in vivo reveals that the combination of constitutive endocytosis via PSMA, and the use of a long half-life isotope, such as Zr-89, will result in SBRs 100-fold higher than is currently possible. Or specific aims include chemical optimization of ZWGPI, in vivo validation, cGMP manufacture under 21 CFR 211/212, and a set of first-in-human trials in men undergoing prostate cancer staging and resection. To accomplish these ambitious aims, we have assembled an international team of experts. We also leverage a unique infrastructure at BIDMC. The newly opened Translational Cancer Imaging Facility (TCIF) is capable of manufacturing IND-eligible optical contrast agents and PET radiotracers under both 21 CFR 211 and 21 CFR 212 cGMP compliance. Of special note, ZW800-1, the zwitterionic NIR fluorophore on which this study is based, was also manufactured in the TCIF and has already been through the FDA IND process. Thus the regulatory path for ZWGPI is well defined at the outset and budgeted appropriately in our application. Completion of our specific aims has the potential to revolutionize prostate cancer care by providing improved PET/MRI staging and, if the chosen definitive treatment is surgery, real-time intraoperative guidance.

描述（由申请人提供）：前列腺癌提出了一个难题。一方面，绝大多数肿瘤在生物学上是懒惰的，可能不需要治疗。另一方面，在手术期间发现肿瘤在局部进展需要积极的治疗治疗。即使有这个难题，分子成像也有可能对患者护理产生巨大影响。为了进行分期，宠物/MRI可以识别不再是器官夹具的肿瘤，从而使男性免于徒劳的手术。对于那些是手术候选者的男性，通过近红外（NIR）荧光进行光学成像可以在前列腺切除期间提供实时引导，重要的是，重要的是突出显示囊外延伸或透射转移的区域。但是，为了实现这两个目标，需要一项将癌细胞检测提高至少100倍以比常规手段提高100倍的技术。指导这项研究的假设是，定义为具有中性和几何平衡的交替阳性和负电荷的分子的Zwitteric对比剂和放射性示例将提供分子成像的对数水平的改进。该假设基于使用小分子，蛋白质和纳米颗粒系统的观察结果。在每种情况下，际电离子分子均表现出极低的非特异性结合与正常组织和器官。而且，当设计以表现出快速，仅肾脏清除率时，完全从体内消除了未结合的剂量，从而导致高SBR。我们研究的重点是前列腺特异性膜抗原（PSMA），这是一种II型膜受体，我们以前已经开发了高亲和力（2和9 nm）的小分子靶向GPI。我们将创建具有光学（800 nm NIR荧光）和PET（ZR-89的脱氧胺螯合）官能团（ZR-89）（ZWGPI）的GPI的zwittionic版本。 ZWGPI在体内性能的数学建模表明，通过PSMA组成型内吞作用的组合以及使用长的半衰期同位素（例如ZR-89）将导致SBRS比当前可能高100倍。或具体目的包括ZWGPI的化学优化，体内验证，CGMP 2111/212下的CGMP制造以及一套接受前列腺癌分期和切除的男性中的首次在人类试验中。为了实现这些雄心勃勃的目标，我们组建了一个国际专家团队。我们还利用BIDMC的独特基础架构。新开放的转化癌成像设施（TCIF）能够在21 CFR 211和21 CFR 212 CGMP合规中生产合格的光学对比剂和PET放射性示例。特别值得注意的是，ZW800-1是该研究所基于的ZWITTERICINIC NIR荧光团，也是在TCIF中制造的，并且已经通过FDA IND过程。因此，在我们的应用中，ZWGPI的监管路径在一开始就得到了很好的定义和预算。我们特定目标的完成有可能通过提供改进的PET/MRI分期来彻底改变前列腺癌护理，如果选择的确定治疗是手术，则可以实时术中指导。