Fluorescence Image-Guided Near Infrared (NIR) Photodynamic Therapy (PDT) Agent

描述(申请人提供)：Photolitec的专利技术专注于开发用于肿瘤成像、图像引导手术和/或光动力疗法(PDT)的改进试剂。提议的STTR方案包括荧光图像引导的光动力疗法，一种“既看又治疗”的方法。这种在800 nm附近具有长波吸收的荧光成像化合物对于图像引导治疗(光动力疗法或手术+光动力疗法)治疗各种肿瘤，特别是大而深的肿瘤是非常有用的。由于其非放射性的性质，目前正在探索用于人类的荧光断层扫描将在肿瘤诊断中产生重大影响。综上所述，这些化合物可用于肿瘤检测、监测肿瘤反应、评估疾病和图像引导治疗。罗斯韦尔帕克癌症研究所(RPCI)开发的近红外光敏剂(PS)技术被转移到Photite，LLC(RPCI的剥离公司)是高效的，表现出大的斯托克斯位移，并且没有表现出任何显著的毒性。因此，进一步开发的成功率很高。由于-3位存在一个手性中心，即基于细菌氯的PS(787 Nm)，它以1：1的比例以R-和S-异构体的混合物形式存在。这两种异构体的体外/体内PDT效率与母体PS(异构体混合物)相似，没有任何显著的皮肤光毒性，这是大多数基于卟啉的PS的主要缺点[例如Photofrin和m-THPC(FOSCAN)]。然而，PS作为异构体混合物或作为纯R-和S-异构体的详细药代动力学(PK)/药效学(PD)尚未被研究。基于有限的初步结果，目前还不清楚是追求同分异构体混合物的发展，还是追求单个异构体的发展。因此，I/II期研究分为两部分：第一阶段：(A)利用已在荷Colon26脑部肿瘤(U87，Gl261，9L)和头颈部(SCC)肿瘤的小鼠中建立的近红外PS及其立体异构体(R-和S-)的治疗参数，并研究其在荧光成像和光动力疗法中的作用；(B)研究PS及其立体异构体对小鼠的正常器官毒性；(C)与美国食品和药物管理局开会，选择PS并据此计划进行第二阶段研究的毒理学研究。第二阶段：(A)使用在GLP设施中配制的GMP制造的PS，用于在选定的肿瘤模型(第一阶段)中可变光剂量计的PDT疗效，(B) 根据美国FDA的要求，研究PS在两种动物物种中的毒性和PK/PD研究，最后，(C)向FDA提交申请，进行第一阶段的人体临床试验。

DESCRIPTION (provided by applicant): Photolitec's patented technology is focused on developing improved agents for tumor- imaging, image-guided surgery and/or photodynamic therapy (PDT). The proposed STTR proposal includes fluorescence-image guided PDT, a "See and Treat" approach. The fluorescence imaging compound with long wavelength absorption near 800 nm should be extremely useful for image-guided therapy (PDT alone or surgery + PDT) for treating a variety of tumors, especially large and deeply seated tumors. Due to its non-radioactive nature, the fluorescence tomography, currently being explored for human use, will have a significant impact in tumor diagnosis. In summary, such compounds can be used for tumor detection, monitoring the tumor response, assessing disease and image-guided therapy. The NIR photosensitizer (PS) technology developed at Roswell Park Cancer Institute (RPCI) is transferred to Photolite, LLC (a spin-off company of RPCI) is highly effective, exhibit a large Stokes shift and does not show any significant toxicity. Therefore, the success rate for further development is high. Due to the presence of a chiral center at position-3, the bacteriochlorin-based PS (787 nm), it exists as a mixture of R- & S- isomers in a 1:1 ratio. The in vitro/in vivo PDT efficacy of both the isomers was similar to the parent PS (isomeric mixture) without any significant skin phototoxicity, a major drawback associated with most of the porphyrin-based PS [e.g. Photofrin and m-THPC (Foscan)]. However, a detailed Pharmacokinetics (PK)/ Pharmacodynamics (PD) of the PS as an isomeric mixture or as a pure R- and S- isomers has not been investigated. On the basis of limited preliminary results, it is not yet clear whether to pursue the development of the isomeric mixture or the individual isomers. Therefore, the Phase I/II study has been divided in two parts: Phase I: (a) To use the treatment parameters of NIR PS and its stereoisomers (R- & S-) already established in mice bearing Colon26 tumors to brain (U87, Gl261, 9L) and head & neck (SCC) tumors and investigate its utility in fluorescence-imaging and PDT (b) To investigate normal organ toxicity of the PS and its stereoisomers in mice and (c) Have a meeting with FDA, select the PS and plan toxicological studies for Phase II studies accordingly. Phase II: (a) To use the GMP manufactured PS, formulated in a GLP facility for PDT efficacy in the selected tumor model (Phase I) at variable light dosimeter, (b) To investigate toxicity and PK/PD studies of the PS in two animal species following the US FDA requirements and finally, (c) Submit the application to FDA for Phase I human clinical trials.