Treatment of Glioblastoma: the combination of fluorescence guided surgery and photodynamic therapy

摘要： 以前资助的STTR(快速通道第一阶段/第二阶段，临床前研究)项目(R41/R42 CA173980-01A) 帮助我们开发了所需的近红外PS(Photobac)，在癌症成像和治疗方面具有巨大的潜力。 在GMP装置上还建立了一种合成Photobac的有效方法。追随美国 FDA指南、不同剂量Photobac的药代动力学(PK)、药效学(PD)和毒性 在小鼠、大鼠和狗身上也进行了研究。组织病理学结果未显示任何器官毒性。PhotoBack 即使是比治疗剂量高20倍的剂量(治疗所需的单一剂量)也不是致命的。不是 甚至在高于预期治疗剂量的情况下，也观察到代谢物的形成和器官毒性。这个 C-14Photobac在不同时间点的生物分布也被测定在小鼠和大鼠体内[7，8]。结果 用C-14Photobac在大鼠和小鼠身上的荧光结果表明Photobac穿过了血脑 屏障(BBB)。 美国FDA对我们要求使用Photobac治疗胶质瘤的Pre-IND反应积极 令人愉快和兴奋(申请号#PIND 136905)。根据FDA审查委员会的建议， 人类患者I期方案已经完成。Nir PS Photobac也收到了一份《孤儿》 美国FDA对胶质母细胞瘤成像和治疗的药物状态(荧光引导手术+ 复发肿瘤的PDT)(#DRU-2017-6153)，这进一步鼓励我们将这项技术转移到 第一阶段人体临床试验。为了实现我们的目标，拟议的研究(SBIR：临床前和临床) 目标分为以下几个方面： 目的1(A)：研究Photobac在大鼠脑胶质瘤模型中的PDT疗效，并利用SimPhotek的专利技术 计算设备FPDosi™(Beeson等人J·比默德。选择。24(3)、035006、2019年)将光剂量与 实验。有关细节，请参阅SimPhotek的支持函。目标1(B)：编制 Photobac CMC(化学、制造和控制)、药物制剂、药材和药物的稳定性 IND的产品、分析细节、PK/PD、毒性、体外和体内数据以及I期临床方案 提交给美国FDA的荧光图像引导手术+光动力疗法治疗胶质母细胞瘤。IND的成本 投稿费用将由Photolitec，LLC支付。 目的2：编制PS(Photobac)定制的近红外激光仪器(787 nm，与 Biolitec的帮助)，遵循美国FDA的指南，并提交审批(IND-AIM联合1)。 目的3：应用Photobac-PDT、荧光引导治疗(手术+PDT)进行I期试验 在单一光剂量和不同药物剂量下选择最佳治疗参数。 目的4：提供胶质母细胞瘤、相应的非肿瘤组织、未经治疗的肿瘤、 Photobac-PDT治疗肿瘤和既往手术、化疗、放疗和治疗后复发的肿瘤 化疗，使用3D细胞培养系统的Photobac特异性，以及STAT3交联物分析。 目的5：建立患者肿瘤(不同阶段)种植的细胞摄取之间的相关性 小鼠，光诱导的STAT3二聚化和长期的PDT反应[7]。将这些发现转化为 提高胶质母细胞瘤患者的最佳治疗参数(S)。

ABSTRACT: The previously funded STTR (Fast Track Phase I/II, preclinical studies) project (R41/R42 CA173980-01A) helped us in developing desired NIR PS (Photobac) with a great potential for both cancer imaging and therapy. An efficient method for the synthesis of Photobac was also established in a GMP facility. Following the US FDA guidelines, the pharmacokinetic (PK), pharmacodynamic (PD) and toxicity of Photobac in various doses were also investigated in mice, rats and dogs. Histopathology results did not show any organ toxicity. Photobac even at a 20-fold higher than the therapeutic dose (single dose needed for the treatment) was not lethal. No metabolite formation and organ toxicity even at higher than the desired therapeutic dose was observed. The biodistribution of C-14 Photobac at variable time points was also determined in mice and rats [7, 8]. Results with C-14 Photobac in rats and fluorescence results in mice suggest that Photobac crosses the blood brain barrier (BBB). A positive pre-IND response from the US FDA on our request for the use of Photobac to treat Gliomas was pleasing & exciting (Application # PIND 136905). As suggested by the FDA review committee, the revision of human patient Phase I protocol has been accomplished. NIR PS Photobac has also received an “Orphan Drug” status from the US FDA for imaging and therapy of Glioblastoma (fluorescence-guided surgery + PDTof recurrence tumors) (# DRU-2017-6153), which further encouraged us to move this technology to Phase I human clinical trials. To achieve our goal, the proposed study (SBIR: Preclinical and Clinical)) has been divided into following aims: Aim 1 (a): To investigate the PDT efficacy of Photobac in rat glioma model and using Simphotek’s proprietary computational device FPDosi™ (Beeson et al. J. Biomed. Opt. 24(3), 035006, 2019) compare light dose to experiments. Details are presented in the letter of support from Simphotek. Aim 1 (b): To compile the Photobac CMC (chemistry, manufacturing and control), drug-formulation, stability of drug substance and drug product, analytical details, PK/PD, toxicity, in vitro & in vivo data and Phase I clinical protocol for an IND submission to the US FDA for fluorescence image guided surgery + PDT of glioblastoma. The cost of the IND submission will be paid by Photolitec, LLC. Aim 2: To compile the details of PS (Photobac)-customized NIR laser instrument (787 nm, developed with the help of Biolitec) following the US FDA guidelines, and submit it for approval (combined IND-Aim 1]. Aim 3: To perform Phase I trial with Photobac-PDT, fluorescence-guided treatment (surgery + PDT) of glioblastoma at a single light dose and variable drug doses for selecting the best treatment parameters. Aim 4: To provide tissue samples from glioblastoma, corresponding non-tumor tissue, untreated tumors, Photobac-PDT treated tumors and recurrent tumors after previous surgery, chemotherapy, radiation and chemotherapy treatment, for Photobac specificity using 3D cell-culture system, and STAT3 crosslinks analysis. Aim 5: Establish a correlation between the cell-uptake on patients’ tumors (at various stages) implanted in mice, photo-induced STAT3 dimerization and a long-term PDT response [7]. Translate these findings to enhance the optimal treatment parameter(s) of glioblastoma patients.