An urinary drug disposing approach for treatment of bladder Cancer

项目摘要 大多数膀胱癌（BC）患者在早期阶段被诊断出来。超过80%的病例是非肌肉型的 侵入性BC（NMIBC）。标准的治疗方法包括手术切除肿瘤，然后进行膀胱内灌注 免疫疗法、卡介苗（BCG）或膀胱内化疗（ITC），以消除残留 癌细胞这涉及通过导管将BCG或药物溶液直接滴入膀胱。然而，在这方面， 癌症复发率仍然高得不可接受（50-80%）。另一方面，人们越来越感兴趣， 保留不适合根治性膀胱切除术的肌肉浸润性膀胱癌（MIBC）患者的膀胱， 国贸中心。BCG和ITC有其局限性。治疗是当地的。药物溶液无法到达位于 在上尿路患者通常需要在给药后不久排尿。导管插入 手术是侵入性的，可能会导致感染和泌尿系统症状，导致患者不良反应。 合规目前，BCG也存在短缺。该项目的目标是开发一种方法， 克服BC疗法的显著药物递送障碍，以改善治疗和生存结果。一 肽的快速肾清除可有利于将治疗导向泌尿系统（URS）。我们 提出了一种生物惰性肽（Bdd）来克服药物传递障碍。Bdd可以通过静脉注射， 而不是膀胱内注射使用Bdd作为载体显示出促进药物，如mertansine（DM 1）和 多柔比星（DOX），仅通过肾脏清除率消除，即使不是检测不到， 在主要器官中沉积。我们假设，这个平台，作为ITC的替代品，将提供一个紧迫的 需要更全面、更有效的治疗。这种尿药处理（UDD）的优点 系统包括：（1）在整个URS中持续给药，（2）延长膀胱停留时间 （治疗持续时间），和（3）微创应用。如果成功，这种方法还将避免 导管插入术，提高患者的生活质量，并降低住院费用。我们的具体目标将侧重于 临床前和转化研究：（目的1）研究所需的理化性质（包括 官能团、长度和表面电荷）和给药参数（输注速率和体积）。 新开发的Bdd类似物Bds，具有改进的UDD性质，用于精确药物递送到URS; 和（目的2）评估DM 1-Bds缀合物用于BC治疗的治疗功效和解剖学灵活性。 我们将评估DM 1-Bds单独或与pembrolizumab联合使用，pembrolizumab是一种免疫检查点抑制剂， 用于治疗NMIBC和MIBC。免疫分析将解决抗- 肿瘤活性。这些信息对于显著改善治疗结果至关重要。与附加 我们还预见到，我们的UDD方法将具有不同寻常的可转座性，并可用于治疗其他 疾病（例如，膀胱感染），简单地通过将连接到肽序列的药物替换为 抗生素

Project Summary Most bladder cancer (BC) patients are diagnosed at an early stage. More than 80% of cases are non-muscle invasive BC (NMIBC). The standard treatment involves removing the tumors surgically, followed by intravesical immunotherapy, bacillus Calmette-Guérin (BCG), or intravesical chemotherapy (ITC) to eradicate residual cancer cells. This involves direct instillation of the BCG or drug solution into the bladder via a catheter. However, the cancer recurrence rate is still unacceptably high (50-80%). On the other hand, there is a growing interest in preserving the bladders of muscle invasive BC (MIBC) patients who are ineligible for radical cystectomy with ITC. BCG and ITC have limitations. The treatments are local. The drug solution is unable to reach tumors located in the upper urinary tract. Patients often need to void shortly after drug administration. The catheterization procedure is invasive, which can potentially cause infection and urinary symptoms, resulting in poor patient compliance. Currently, there is also a shortage of BCG. The goal of this project is to develop an approach to counter the significant drug delivery obstacles of BC therapy to improve treatment and survival outcomes. A peptide’s rapid renal clearance can be advantageous for directing treatments to the urinary system (URS). We propose a bio-inert peptide (Bdd) to overcome the drug-delivery barriers. Bdd can be given intravenously rather than intravesically. The use of Bdd as a carrier was shown to promote drugs, such as mertansine (DM1) and doxorubicin (DOX), to be eliminated exclusively via renal clearance, with minimal—if not undetectable— deposition in major organs. We hypothesize that this platform, used as an alternative to ITC, will offer an urgently needed treatment that is more complete and effective. The advantages of such a urinary drug disposing (UDD) system include: (1) continuous drug flow throughout the entire URS, (2) prolongation of bladder-dwelling time (treatment duration), and (3) minimally invasive application. If successful, this approach will also avoid catheterization, improve patient quality of life, and reduce hospitalization costs. Our Specific Aims will focus on preclinical and translational studies to: (Aim 1) investigate the desired physicochemical properties (including functional group, length, and surface charges) and administration parameters (infusion rate and volume) of a newly developed Bdd analogue, Bds, with an improved UDD property, for precision drug delivery to the URS; and (Aim 2) evaluate the therapeutic efficacy and anatomic flexibility of a DM1-Bds conjugate for BC treatment. We will assess DM1-Bds alone or in combination with pembrolizumab, an immune checkpoint inhibitor approved by the Food and Drug Administration, for treating both NMIBC and MIBC. Immune profiling will address the anti- tumor activities. This information will be crucial for significantly improving treatment outcomes. With additional advancements, we also foresee our UDD approach will be unusually transposable and useful for treating other diseases (e.g., bladder infections), simply by replacing the drugs attached to the peptide sequence with antibiotics.