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

ZW800-1：第一个用于癌症成像的两性离子近红外荧光团

• 批准号: 9254979
• 负责人: John V Frangioni
• 金额: $ 98.94万
• 依托单位: CURADEL, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-08 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254979
• 关键词: Abdomen; Academic Medical Centers; Air; Antibodies; Award; Binding; Carboxylic Acids; Cessation of life; Chemicals; Clinical; Clinical Research; Clinical Trials; Collaborations; Consultations; Contrast Media; Controlled Environment; Dose; Esters; Europe; European; Exhibits; Extinction (Psychology); Family; Flare; Freeze Drying; Goals; Heavy Metals; Home environment; Hour; Human; Human Volunteers; Hybrids; Image-Guided Surgery; Injectable; Investigational Therapies; Investments; Letters; Light; Litigation; Maleimides; Malignant Neoplasms; Medicine; Morbidity - disease rate; Netherlands; Normal tissue morphology; Operative Surgical Procedures; Organ; Patients; Pelvis; Pharmaceutical Preparations; Pharmacists; Pharmacologic Substance; Phase; Plants; Positioning Attribute; Powder dose form; Process; Property; Proteins; Publications; Renaissance; Renal clearance function; Research; Research Infrastructure; Residual state; Ships; Signal Transduction; Site; Small Business Innovation Research Grant; Solvents; Stainless Steel; Sterility; Study Subject; Surgeon; System; Technology; Testing; Time; Toxic effect; Toxicology; Ureter; Urine; Vial device; Visit; cancer imaging; cancer surgery; commercialization; cost; experience; fluorophore; genotoxicity; imaging system; innovation; interest; intravenous injection; nanoparticle; novel; peptidomimetics; polyion; pre-clinical; programs; quantum; research clinical testing; safety study; small molecule; success; uptake

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.”

7。项目摘要/摘要 使用不可见的近红外（NIR）光进行图像引导的手术，处于文艺复兴时期。多种的 商业成像系统，包括Curadel的最先进的Flare®系统，可用于预先 临床，兽医和人类手术。但是，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。 库拉德尔（Curadel）发明了一个新型的NIR荧光团系列，称为“ Zwitterionic”。更确切地说是 几何平衡，中性的，多元双胸酰胺。 Zwitterion NIR荧光团 单静脉内表现出极低的非特异性结合和在正常组织和器官中的摄取 注射，但具有极高的延伸系数，量子产率和信号强度。因为这些 特性，Zwitterion NIR荧光团创造了最高的信号背景比（SBR）。 zwitterionic nir荧光团有两种直接的临床用途，使它们如此吸引人 商业上。首先，它们可以通过N-羟基糖磺胺（NHS）在一个化学步骤中结合。 酯，四氟哲学（TFP）酯或对任何癌症的小分子，辣椒剂，酯类酯， 抗体，蛋白质或纳米颗粒，从而产生了用于癌症手术的靶向NIR荧光对比剂。 其次，当以最简单的羧酸形式注入时，zwitterion Nir荧光团暴露了100％肾脏 清除和消除尿液。这会导致输尿管在近后几个小时变成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免输尿管的能力 腹部和骨盆的手术。输尿管损坏虽然罕见，但却导致了非常高的成本，并且 患者发病率。 由于其临床潜力，ZW800-1被NCI的实验视为高价值资产 治疗学（下一个）程序，并被接受为第一个人类区域。与FDA协商 下一个程序为完整的两种毒理学包，遗传毒性包和诱变付费支付 包装，所有这些都是负面的（请参阅附录）。由于ZW800-1，以及Curadel的毒品组合 315个独特的化学实体，是手术领域中最重要的公司访问了我们，大多数公司 对投资和/或分销感兴趣。但是，我们收到的信息是一致的 - 投资只有在完成ZW800-1的首次人类临床试验之后才能进行。 在此直接到相2（D2P2）SBIR应用中，我们解决当前困境的方法是 系统。 ISO-7下的ZW800-1的CGMP制造，无菌填充物，包括ISO下的冻干化 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 荷兰的医疗中心（LUMC）。目标的完成将定位库拉德尔以执行较大的 与手术空间中的主要参与者的分销/投资交易，从而跨越了“死亡谷”。