(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

• 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
• 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

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）：前列腺癌是一个难题。一方面，绝大多数肿瘤在生物学上是惰性的，可能不需要治疗。另一方面，在手术中发现局部进展的肿瘤需要积极治疗才能治愈。即使存在这个难题，分子成像仍有可能对患者护理产生巨大影响。对于分期，PET/MRI可以识别出不再受器官限制的肿瘤，从而使男性免于无用的手术。对于需要手术的男性，近红外（NIR）荧光光学成像可以在前列腺切除术期间提供实时指导，重要的是，可以突出囊外延伸或转移的区域。然而，要实现这两个目标，需要一种比传统方法提高至少100倍的癌细胞检测技术。指导本研究的假设是两性离子造影剂和放射性示踪剂，定义为具有电中性和几何平衡交替正负电荷的分子，将提供对数级分子成像的改进。这个假设是基于我们小组对小分子、蛋白质和纳米粒子系统的观察。在每种情况下，两性离子分子对正常组织和器官表现出极低的非特异性结合。而且，当设计成表现出快速，仅肾清除时，未结合的剂量完全从体内消除，导致高SBR。我们的研究重点是前列腺特异性膜抗原（PSMA），这是一种II型膜受体，我们之前已经开发了高亲和力（2和9 nM）小分子靶向配体GPI。我们将创建具有光学（800 nm近红外荧光）和PET （Zr-89的去铁胺螯合）官能团（ZWGPI）的两性离子版本的GPI。ZWGPI在体内性能的数学模型表明，通过PSMA的本构性内吞作用和使用长半衰期同位素（如Zr-89）的组合将导致sbr比目前可能的高100倍。具体目标包括ZWGPI的化学优化，体内验证，根据21 CFR 211/212生产cGMP，以及一系列首次在前列腺癌分期和切除的男性中进行的人体试验。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独特的基础设施。新开业的转化癌症成像设施（TCIF）能够生产符合21 CFR 211和21 CFR 212 cGMP要求的ind标准的光学造影剂和PET放射性示踪剂。特别值得注意的是，本研究所依据的两性离子近红外荧光团ZW800-1也是在TCIF生产的，并且已经通过了FDA IND流程。因此，ZWGPI的监管路径在一开始就被很好地定义，并在我们的应用程序中进行了适当的预算。通过提供改进的PET/MRI分期，如果选择最终治疗是手术，实时术中指导，我们的特定目标的完成有可能彻底改变前列腺癌的治疗。