ZW800-1: The 1st Zwitterionic NIR Fluorophore for Cancer Imaging & Ureter Mapping

7.项目总结/摘要 使用不可见近红外（NIR）光的图像引导手术正处于复兴之中。多 商用成像系统，包括Curadel最先进的FLARE®系统，可用于 临床、兽医和人体外科。然而，该领域的最终成功将取决于创新 解决重要临床问题的NIR荧光团。 Curadel发明了一种新的近红外荧光团家族，称为“两性离子”。更准确地说， 几何平衡的、电中性的、多离子聚甲川吲哚菁。两性离子近红外荧光团 在单次静脉注射后， 注入，但具有极高消光系数、量子产率和信号强度。因为这些 两性离子近红外荧光团具有最高的信号背景比（SBR）。 两性离子近红外荧光团有两个直接的临床用途，使他们如此有吸引力 在商业上。首先，它们可以通过N-羟基琥珀酰亚胺（NHS）在一个化学步骤中缀合 酯、四氟苯基（TFP）酯或马来酰亚胺与任何靶向癌症的小分子，肽模拟物， 抗体、蛋白质或纳米颗粒，从而产生用于癌症手术的靶向NIR荧光造影剂。 第二，当以其最简单的羧酸形式注射时，两性离子NIR荧光团表现出100%的肾功能。 清除和排泄到尿液中。这导致输尿管在手术后几个小时内变成NIR荧光。 单次静脉注射，从而为外科医生提供了在癌症期间避开输尿管的能力 腹部和骨盆的外科手术。输尿管损伤虽然不常见，但会导致非常高的成本， 患者发病率。 由于其临床潜力，ZW 800 -1被NCI的实验室视为高价值资产。 治疗（NExT）计划，并被接受到第一次在人类道。经与FDA协商， NExT计划支付了完整的两个物种毒理学包、遗传毒性包和致突变性 包，均为阴性（见附录）。由于ZW 800 -1和Curadel的药物组合超过 315个独特的化学实体，手术领域最重要的公司都访问过我们， 对投资和/或分销感兴趣。但我们收到的信息是一致的- 只有在ZW 800 -1的首次人体临床试验完成后，才会进行投资。 在这个直接到阶段2（D2 P2）SBIR应用程序中，我们解决当前困境的方法是 系统性根据ISO-7进行ZW 800 -1的cGMP生产，根据ISO进行无菌灌装-成品（包括冻干） 5/4.8，然后在我们的主要学术合作网站莱顿大学进行1A/1B期临床研究 荷兰医学中心（LUMC）。目标的完成将使Curadel能够执行相当大的 分销/投资与外科领域的主要参与者打交道，从而跨越“死亡谷”。

7. PROJECT SUMMARY/ABSTRACT Image-guided surgery using invisible near-infrared (NIR) light is in the midst of a renaissance. Multiple commercial imaging systems, including Curadel's state-of-the-art FLARE® system, are available for pre- clinical, veterinary, and human surgery. However, the ultimate success of the field will depend on innovative NIR fluorophores that solve important clinical problems. Curadel has invented a novel family of NIR fluorophores termed “zwitterionic.” More precisely, they are geometrically balanced, electrically-neutral, polyionic polymethine indocyanines. Zwitterionic NIR fluorophores exhibit extremely low non-specific binding and uptake in normal tissues and organs after a single intravenous injection, yet have extremely high extinction coefficient, quantum yield, and signal strength. Because of these properties, zwitterionic NIR fluorophores create the highest possible signal-to-background ratio (SBR). There are two immediate clinical uses for zwitterionic NIR fluorophores that make them so attractive commercially. First, they can be conjugated in one chemical step, through either N-hydroxysuccinimide (NHS) esters, tetrafluorophenyl (TFP) esters, or maleimide to any cancer-targeted small molecule, peptidomimetic, antibody, protein, or nanoparticle thus creating a targeted NIR fluorescent contrast agent for cancer surgery. Second, when injected in their simplest carboxylic acid form, zwitterionic NIR fluorophores exhibit 100% renal clearance and elimination into urine. This causes the ureters to become NIR fluorescent for several hours after a single intravenous injection, thus providing surgeons with the ability to avoid the ureters during cancer surgeries of the abdomen and pelvis. Ureter damage, while uncommon, leads to extraordinarily high cost and patient morbidity. Because of its clinical potential, ZW800-1 was deemed a high value asset by the NCI's Experimental Therapeutics (NExT) Program and was accepted into the first-in-human tract. In consultation with the FDA, the NExT Program paid for a complete two-species toxicology package, a genotoxicity package, and mutagenicity package, all of which were negative (see Appendix). Because of ZW800-1, and Curadel's drug portfolio of over 315 unique chemical entities, the most important companies in the field of surgery have visited us, and most are interested in investment and/or distribution. The message we have received, though, is consistent – investment will only come after first-in-human clinical trials of ZW800-1 are completed. In this direct-to-Phase 2 (D2P2) SBIR application, our approach to solve our current dilemma is systematic. cGMP manufacturing of ZW800-1 under ISO-7, aseptic fill-finish including lyophilization under ISO 5/4.8, then a Phase 1A/1B clinical study at our major academic collaboration site, the Leiden University Medical Center (LUMC) in the Netherlands. Completion of the aims will position Curadel to execute a sizeable distribution/investment deal with a major player in the surgical space, and thus cross the “valley of death.”