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

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，并且可能不需要治疗。另一方面，在手术过程中发现局部晚期的肿瘤需要积极的治疗才能治愈。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。对于分期，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。对于手术候选人，通过近红外（NIR）荧光的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，突出囊外延伸或转移的区域。然而，为了实现这两个目标，需要一种技术，将癌细胞检测提高至少100倍于传统手段。 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）将在分子成像中提供对数水平的改善。这一假设是基于我们小组使用小分子、蛋白质和纳米颗粒系统的观察。在每种情况下，两性离子分子表现出极低的非特异性结合正常组织和器官。而且，当被设计为表现出快速的、仅肾脏清除时，未结合的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，我们以前已经开发了高亲和力（2和9 nM）的小分子靶向配体，称为GPI。我们将创建具有光学（800 nm NIR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的体内性能的数学建模揭示了通过PSMA的组成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。或者具体目标包括ZWGPI的化学优化，体内验证，根据21 CFR 211/212生产cGMP，以及在接受前列腺癌分期和切除术的男性中进行的一系列首次人体试验。 为了实现这些宏伟目标，我们组建了一支国际专家团队。我们还利用BIDMC独特的基础设施。新成立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合格光学造影剂和PET放射性示踪剂。特别值得注意的是，本研究所基于的两性离子近红外荧光团ZW 800 -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得到了很好的定义，并在我们的应用程序中得到了适当的预算。 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护理。

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.