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

描述（由申请人提供）：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）的改进剂。拟议的STTR提案包括荧光图像引导的PDT，一种“看和治疗”的方法。在800 nm附近具有长波长吸收的荧光成像化合物对于治疗各种肿瘤，特别是大的和深的肿瘤的图像引导治疗（单独的PDT或手术+ PDT）应该是非常有用的。由于其非放射性性质，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。总之，此类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。Roswell Park癌症研究所（RPCI）开发的NIR光敏剂（PS）技术转移到Photolite，LLC（RPCI的分拆公司），该技术非常有效，表现出较大的斯托克斯位移，并且没有显示出任何显著的毒性。因此，进一步开发的成功率很高。 由于在位置-3处存在手性中心，基于菌绿素的PS（787 nm），其以1：1比例的R-和S-异构体的混合物存在。两种异构体的体外/体内PDT功效与母体PS（异构体混合物）相似，没有任何显著的皮肤光毒性，这是与大多数基于卟啉的PS [例如Photofrin和m-THPC（Foscan）]相关的主要缺点。然而，尚未研究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）。根据有限的初步结果，尚不清楚是继续开发异构体混合物还是单个异构体。因此，I/II期研究分为两部分：I期：（a）使用已经在携带Colon 26肿瘤至脑的小鼠中建立的NIR PS及其立体异构体（R- & S-）的治疗参数（U87，G1261，9 L）和头颈部（SCC）肿瘤，并研究其在荧光成像和PDT（B）中的效用研究PS及其立体异构体在小鼠中的正常器官毒性，以及（c）与FDA举行会议，选择PS并相应地计划II期研究的毒理学研究。 第二阶段：（a）使用GMP制造的PS，在GLP设施中配制，用于在可变光剂量计下在选定的肿瘤模型（I期）中的PDT功效，（B） 按照美国FDA的要求，在两种动物物种中研究PS的毒性和PK/PD研究，最后，（c）向FDA提交I期人体临床试验的申请。

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.