Singlet Oxygen-cleavable Prodrugs for Treating Non-Muscle Invasive Bladder Cancers

膀胱癌（2021年估计有83，730例新发病例和17，200例死亡）是独一无二的，因为大多数（70-80%） 患者被诊断为早期非肌层浸润性膀胱癌（NMIBC）。NMIBC首先通过 经尿道切除术（TUR），然后辅助经尿道治疗，如膀胱内BCG和 化疗，用于晚期高危患者。然而，复发仍然是一个重要的问题。 问题.自从BCG被FDA批准用于膀胱癌以来，NMIBC治疗没有突破 1990年治疗。去年，FDA批准pembrolizumab用于治疗BCG无反应，高风险 NMIBC，但它是非常昂贵的，其完全响应率不是很令人满意。这几天 卡介苗缺乏已成为临床上的一个问题。我们的长期目标是在临床上开发一种 可翻译的NMIBC治疗策略，以有效和选择性地杀死癌细胞，而不会对 正常膀胱组织我们的假设是，一个单重态氧（SO）的激活， 前药在癌细胞的线粒体中被HAL（己基-5-氨基乙酰丙酸酯）-PDT有效活化， 大大提高了HAL-PDT的治疗效果，同时附带损伤最小。最近，我们证明了， 在分子内和分子间活化方面提出了这种新的SO-可活化的前药概念 礼节.预期绿色光和膀胱内给药的组合可避免附带损害 与传统PDT不同，这项拟议工作的目标是：1）制定SO- 用于NMIBC的临床上使用的抗癌药物的可活化前药，和2）证明该前药的增强的功效， 在体外和体内模型中的联合治疗。将使用膀胱癌的原位大鼠模型 以更好地模拟人类NMIBC的生理学。提出了三个具体目标：目标1）开发线粒体- 用于NMIBC的临床使用的药物的靶向和SO-可活化的前药，目的2）确定摄取和 使用3D细胞培养物和健康膀胱（大鼠和兔）的组合效果，以及目的3）确定 使用原位大鼠膀胱癌的联合治疗的抗癌效果和局部副作用 模型该项目在概念和技术方面都具有很高的创新性。这是一种新颖的方法， 使用高度多学科和综合策略解决重要的临床问题。如果成功， 拟议的研究将提供新的有效的治疗策略和前药治疗NMIBC与高 快速临床转化的可能性，因为HAL和抗癌药物历来用于NMIBC。 由于光学和经尿道手术技术的进步以及膀胱独特的可及性， 在临床实践中实施该策略没有重大技术障碍。我们一直在咨询 与执业泌尿外科临床医生合作，使我们的战略转向临床翻译。我们的策略也可以是 适用于许多其他癌症（脑、胃肠道恶性肿瘤、宫颈癌）微转移的术后治疗 和卵巢癌），HAL已被用于荧光诊断。

Bladder cancer (estimated 83,730 new cases and 17,200 death in 2021) is unique in that most (70-80%) of patients are diagnosed with early-stage, non-muscle invasive bladder cancer (NMIBC). NMIBC is first treated by transurethral resection (TUR) and then adjuvant transurethral therapies, such as intravesical BCG and chemotherapy, for patients with high risk for advanced stages. However, recurrence remains a significant problem. There has been no breakthrough in NMIBC treatment since BCG was FDA-approved for bladder cancer treatment in 1990. Last year, the FDA approved pembrolizumab for treating BCG-unresponsive, high-risk NMIBCs, but it is very expensive and its complete response rate is not very satisfactory. These days, the shortage of BCG has become a problem in clinical practice. Our long-term goal is to develop a clinically translatable NMIBC-treatment strategy to effectively and selectively kill cancer cells without collateral damage to normal bladder tissue. Our hypothesis is that a mitochondria-localizing and singlet oxygen (SO)-activatable prodrug is effectively activated by HAL (hexyl-5-aminolevulinate)-PDT in the mitochondria of cancer cells, thus greatly improving therapeutic efficacy of HAL-PDT with minimal collateral damage. Recently, we proved and advanced this novel SO-activatable prodrug concept in both intramolecular and intermolecular activation manners. The combination of green light and intravesical administration is expected to avoid collateral damage to normal bladder wall unlike traditional PDT. The objectives of this proposed work are 1) to develop SO- activatable prodrugs of clinically used anticancer drugs for NMIBC and 2) to prove enhanced efficacy of this combination treatment in both in vitro and in vivo models. An orthotopic rat model of bladder cancer will be used to better mimic physiology of human NMIBC. Three specific aim are proposed: Aim 1) Develop mitochondria- targeting and SO-activatable prodrugs of clinically used drugs for NMIBC, Aim 2) Determine uptake and the combination effect using 3D cell culture and healthy bladders (rat and rabbit), and Aim 3) Determine the anticancer effects and local side effects of the combination treatment using the orthotopic rat bladder cancer model. This project is highly innovative in both conceptual and technical aspects. It is a novel approach to address an important clinical problem using a highly multidisciplinary and integrative strategy. If successful, the proposed research will provide new effective treatment strategy and prodrugs for treating NMIBC with high likelihood of rapid clinical translation, because HAL and anticancer drugs have historically been used for NMIBC. Due to the advances in optical and transurethral surgical technology and the unique accessibility of bladder, there is no major technical barrier for implementing such strategy to clinical practice. We have been consulting with practicing urological clinicians to gear our strategy towards clinical translation. Our strategy can also be applied to post-surgical treatment of micro-metastasis of many other cancers (brain, GI malignancies, cervical and ovarian cancers), for which HAL has been used for fluorescence diagnosis.