(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(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，很可能不需要治疗。另一方面，手术中发现的局部晚期肿瘤需要积极治疗才能治愈。即使有了这个难题，分子成像也有可能对患者护理产生巨大影响。在分期方面，PET/MRI可以识别不再局限于器官的肿瘤，从而使男性免于徒劳的手术。对于准备接受手术的男性，通过近红外(NIR)荧光进行的光学成像可以在前列腺切除过程中提供实时指导，重要的是，可以突出显示包膜外延伸或转移中的区域。然而，为了实现这两个目标，需要一种将癌细胞检测能力提高至少100倍于传统方法的技术。指导这项研究的假设是，两性离子造影剂和放射性示踪剂，即具有电中性和几何平衡交替正负电荷的分子，将在分子成像中提供对数水平的改进。这一假设是基于我们团队使用小分子、蛋白质和纳米颗粒系统的观察得出的。在每种情况下，两性离子分子都表现出极低的非特异性结合正常组织和器官。而且，当被设计成表现出快速的、仅限于肾脏的清除时，非结合剂量从体内完全消除，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，我们以前已经开发出了称为GPI的高亲和力(2和9 nm)小分子靶向配体。我们将创建两性离子版本的GPI，既具有光学(800 nm近红外荧光)，又具有PET(去铁胺对Zr-89的络合)官能团(ZWGPI)。对ZWGPI在体内的表现进行的数学建模表明，通过PSMA进行的结构性内吞作用与长半衰期同位素(如Zr-89)的使用相结合，将导致SBRs比目前可能的水平高100倍。具体目标包括ZWGPI的化学优化、体内验证、根据21CFR 211/212制造cGMP，以及在接受前列腺癌分期和切除的男性中进行的一系列首例人体试验。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。我们还利用了BIDMC独特的基础设施。新开业的转化癌成像设备(TCIF)能够根据21 CFR 211和21 CFR 212 cGMP标准生产符合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，ZW800-1，这项研究的基础上的两性离子近红外荧光团，也是在TCIF中制造的，并已经通过FDA的IND工艺。因此，ZWGPI的监管路径在一开始就定义得很好，并在我们的应用程序中进行了适当的预算。完成我们的特定目标有可能通过提供改进的PET/MRI分期以及(如果选择的最终治疗是手术)实时术中指导来彻底改变前列腺癌的治疗。