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

膀胱癌(估计2021年新增83,730例，死亡17,200例)的独特之处在于，大多数(70%-80%) 患者被诊断为早期非肌肉浸润性膀胱癌(NMIBC)。NMIBC首先得到的治疗是 经尿道电切术(TUR)，然后辅助性经尿道治疗，如膀胱内卡介苗和 化疗，适用于晚期高危患者。然而，复发仍然是一个重要的问题。 有问题。自从BCG被FDA批准用于膀胱癌以来，NMIBC的治疗一直没有突破 1990年接受治疗。去年，fda批准pembrolizumab用于治疗卡介苗无反应、高风险 NMIBCs，但非常昂贵，其完全应答率不是很令人满意。这些天来， 卡介苗的缺乏已经成为临床实践中的一个问题。我们的长期目标是开发一种临床 可翻译的NMIBC治疗策略，有效和选择性地杀死癌细胞，而不会对 正常的膀胱组织。我们的假设是线粒体定位和单线态氧(SO)可激活 癌细胞线粒体中的HAL(5-氨基酮戊酸)-PDT有效地激活了前药，从而 极大地提高了HAL-PDT的疗效，且附带损伤最小。最近，我们证明了 在分子内和分子间的激活中提出了这种新的可激活的前药概念 礼貌。绿灯和膀胱内给药相结合有望避免附带损害 至正常膀胱壁，与传统的光动力疗法不同。这项拟议工作的目标是1)开发这样的- NMIBC临床用抗癌药物的活性前药和2)证明其增强疗效 体外和体内模型的联合治疗。将使用原位大鼠膀胱癌模型 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)发展线粒体- NMIBC临床用药的靶向和可激活的前药，目的2)确定摄取和 利用3D细胞培养和健康膀胱(大鼠和兔)的组合效应，以及Aim 3)确定 大鼠原位膀胱癌联合治疗的抗癌效果及局部不良反应 模特。该项目在概念和技术方面都具有很高的创新性。这是一种新的方法来 使用高度多学科的综合策略解决一个重要的临床问题。如果成功，则 拟议的研究将为治疗NMIBC伴高血压病提供新的有效治疗策略和前药 快速临床转化的可能性，因为HAL和抗癌药物在历史上一直用于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， 将这一策略应用于临床并不存在重大的技术障碍。我们一直在咨询 与执业的泌尿外科临床医生一起调整我们的战略，以实现临床翻译。我们的战略也可以是 适用于许多其他癌症(脑、胃肠道恶性肿瘤、宫颈癌)术后微转移的治疗 和卵巢癌)，HAL已用于荧光诊断。

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.