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

基本信息

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
项目类别：
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

项目摘要

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. 项目概要/摘要使用不可见近红外 (NIR) 光的图像引导手术正在复兴。商业成像系统，包括 Curadel 最先进的 FLARE® 系统，可用于预然而，该领域的最终成功将取决于创新。近红外荧光团可解决重要的临床问题。 Curadel 发明了一种新型近红外荧光团，称为“两性离子”。几何平衡、电中性、聚离子聚次甲基吲哚菁染料。单次静脉注射后，在正常组织和器官中表现出极低的非特异性结合和摄取注射，但具有极高的消光系数、量子产率和信号强度。由于其特性，两性离子近红外荧光团可产生尽可能高的信号背景比 (SBR)。两性离子近红外荧光团有两个直接的临床用途，这使得它们如此有吸引力首先，它们可以在一个化学步骤中通过 N-羟基琥珀酰亚胺 (NHS) 进行缀合。酯、四氟苯基 (TFP) 酯或马来酰亚胺到任何癌症靶向小分子、肽模拟物、抗体、蛋白质或纳米颗粒，从而创造出用于癌症手术的靶向近红外荧光造影剂。其次，当以最简单的羧酸形式注射时，两性离子 NIR 荧光团表现出 100% 肾清除并排入尿液，这会导致输尿管在数小时内发出近红外荧光。单次静脉注射，从而使外科医生能够在癌症期间避开输尿管腹部和骨盆损伤的手术虽然不常见，但会导致极高的费用和费用。患者发病率。由于其临床潜力，ZW800-1 被 NCI 实验实验室视为高价值资产治疗 (NExT) 计划并在与 FDA 协商后被纳入首次人体道治疗。 NExT 计划支付了完整的两种毒理学包、遗传毒性包和致突变性包包，全部为阴性（见附录），因为ZW800-1和Curadel的药物组合超过。 315 个独特的化学实体，外科领域最重要的公司访问过我们，并且大多数不过，我们收到的信息是一致的—— ZW800-1的首次人体临床试验完成后才会进行投资。在这个直接进入第 2 阶段 (D2P2) SBIR 应用程序中，我们解决当前困境的方法是根据 ISO-7 系统化地进行 ZW800-1 的 cGMP 生产，并根据 ISO 进行无菌灌装（包括冻干）。 5/4.8，然后在我们的主要学术合作地点莱顿大学进行 1A/1B 期临床研究荷兰医疗中心 (LUMC) 的目标的完成将使 Curadel 能够执行相当大的任务。分销/投资与外科领域的主要参与者进行交易，从而跨越“死亡之谷”。