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

用于治疗非肌肉侵袭性膀胱癌的单线态氧可裂解前药

• 批准号: 10665068
• 负责人: Youngjae You
• 金额: $ 41.13万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-13 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665068
• 关键词: Address; Adjuvant; Adjuvant Therapy; Aminolevulinate; Animals; Antineoplastic Agents; Bacillus Calmette-Guerin Therapy; Bladder; Bladder Tissue; Brain; Canada; Cancer Model; Cancer Patient; Cells; Cessation of life; Clinical; Combined Modality Therapy; Cystoscopy; Diagnosis; Diffusion; Disease; Dose; Drug Delivery Systems; Drug Design; Drug Exposure; Drug Kinetics; Drug usage; Excision; FDA approved; Fluorescence; Functional disorder; Goals; Human; Immune; In Vitro; In complete remission; Interruption; Intravesical Administration; Light; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of ovary; Malignant neoplasm of urinary bladder; Medical Care Costs; Micrometastasis; Mitochondria; Mitomycin C; Modeling; Nature; Normal tissue morphology; Operative Surgical Procedures; Optics; Organ; Oryctolagus cuniculus; Outcome; PUVA Photochemotherapy; Patients; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Physiology; Process; Prodrugs; Property; Protocols documentation; Rattus; Recurrence; Regimen; Research; Singlet Oxygen; System; Technology; Time; Transurethral Resection; Treatment Efficacy; Treatment Protocols; Urethra; Urine; Urologist; Work; anti-cancer; cancer cell; cancer therapy; cell killing; chemotherapy; clinical practice; clinical translation; docetaxel; drug action; drug clearance; effective therapy; efficacy evaluation; gemcitabine; high risk; implementation barriers; improved; in vivo Model; indexing; innovation; intravesical; multidisciplinary; non-muscle invasive bladder cancer; novel; novel strategies; optimal treatments; pembrolizumab; pharmacologic; protoporphyrin IX; side effect; stem; three dimensional cell culture; three-dimensional modeling; tool; treatment optimization; treatment strategy; tumor; uptake; urologic

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.

膀胱癌（估计有83,730例新病例和2021年死亡17,200例）是独一无二的 患者被诊断为早期，非肌肉浸润性膀胱癌（NMIBC）。 NMIBC首先由 经尿道切除（TUR），然后再尿道尿道疗法，例如静脉内BCG和 化学疗法，适用于高晚期风险的患者。但是，复发仍然是重要的 问题。自BCG被FDA批准用于膀胱癌以来，NMIBC治疗没有突破 1990年的治疗。去年，FDA批准了Pembrolizumab用于治疗BCG无反应，高风险 NMIBC，但它非常昂贵，并且其完整的响应率不是很令人满意。这些天， 在临床实践中，BCG的短缺已成为一个问题。我们的长期目标是在临床上开发 可翻译的NMIBC治疗策略，可有效，有选择地杀死癌细胞，而不会造成附带损害 正常的膀胱组织。我们的假设是线粒体定位和单线氧（SO）可变 癌细胞线粒体中的HAL（Hexyl-5-氨基乙酸）-pdt有效地激活前药，因此 通过最小的附带损害，大大提高了HAL-PDT的治疗功效。最近，我们证明了 先进的这种新颖的新颖的动物前药概念在分子内和分子间激活中 举止。绿灯和静脉内给药的结合有望避免附带损害 与传统的PDT不同，正常的膀胱壁。这项拟议工作的目标是1） 临床使用的NMIBC抗癌药物的可激活前药和2）证明了这一点的功效 体外和体内模型的组合处理。将使用膀胱癌的原位大鼠模型 更好地模仿人类NMIBC的生理学。提出了三个特定目的：目标1）发展线粒体 - 针对NMIBC的临床使用药物的靶向和可激活的前药，目标2）确定摄取和摄取 使用3D细胞培养和健康膀胱（大鼠和兔子）的组合效应，目标3）确定 使用原位大鼠膀胱癌的组合治疗的抗癌作用和局部副作用 模型。该项目在概念和技术方面都是高度创新的。这是一种新颖的方法 使用高度多学科和综合策略来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治疗策略和前药，用于治疗NMIBC 快速临床翻译的可能性，因为HAL和抗癌药物历史上已用于NMIBC。 由于光学和尿道手术技术的进步以及膀胱的独特可及性， 没有重大的技术障碍来实施这种临床实践的策略。我们一直在咨询 随着执业泌尿科临床医生，将我们的策略置于临床翻译方面。我们的策略也可能是 应用于许多其他癌症（大脑，GI恶性肿瘤，宫颈）的微神经的手术后治疗 和卵巢癌），为其用于荧光诊断。

项目成果

Comparison of red and green light for treating non-muscle invasive bladder cancer in rats using singlet oxygen-cleavable prodrugs with PPIX-PDT.

使用单线态氧可裂解前药与 PPIX-PDT 治疗大鼠非肌肉浸润性膀胱癌的红光和绿光比较。

• DOI: 10.1111/php.13933
• 发表时间: 2024
• 期刊: Photochemistry and photobiology
• 影响因子: 3.3
• 作者: Rahman,KaziMdMahabubur;Kumbham,Soniya;Bist,Ganesh;Woo,Sukyung;Foster,BarbaraA;You,Youngjae
• 通讯作者: You,Youngjae