An urinary drug disposing approach for treatment of bladder Cancer

项目摘要 大多数膀胱癌患者在早期就被诊断出来。超过80%的病例是非肌肉的 侵袭性BC(NMIBC)。标准的治疗方法包括手术切除肿瘤，然后进行膀胱内注射。 免疫疗法、卡介苗(BCG)或膀胱内化疗(ITC)以消除残留 癌细胞。这包括通过导管将卡介苗或药物溶液直接滴入膀胱。然而， 癌症复发率仍然高得令人无法接受(50%-80%)。另一方面，人们对……的兴趣越来越大 保留肌肉侵袭性膀胱癌(MIBC)患者的膀胱 国际贸易中心。BCG和ITC都有局限性。治疗是在当地进行的。药物溶液不能到达肿瘤部位 在上尿路。患者经常需要在服药后不久排出尿液。导尿术 手术是侵入性的，可能会导致感染和泌尿症状，导致患者情况不佳 合规性。目前，卡介苗也出现了短缺。这个项目的目标是开发一种方法来 对抗BC疗法的重大药物输送障碍，以改善治疗和生存结果。一个 多肽的快速肾脏清除有利于指导对泌尿系统(URS)的治疗。我们 提出了一种生物惰性多肽(BDD)来克服药物传递障碍。BDD可以静脉给药而不是 而不是膀胱内注射。使用BDD作为载体被证明可以促进药物，如Mertansine(DM1)和 阿霉素(DOX)，完全通过肾脏清除消除，即使不是无法检测到，也是最小的- 在主要器官中沉积。我们假设这个平台，作为ITC的替代方案，将提供一个紧急的 需要更全面、更有效的治疗。这种尿液药物处置(UDD)的优势 该系统包括：(1)在整个尿路中持续的药物流动；(2)延长膀胱滞留时间 (3)微创应用。如果成功，这种方法还将避免 导尿术，提高患者生活质量，降低住院费用。我们的具体目标将集中在 临床前和转化性研究：(目标1)调查所需的物理化学性质(包括 官能团、长度和表面电荷)和给药参数(输液速率和体积) 新开发的BDD类似物，BDS，具有改进的UDD特性，用于向URS精确递送药物； 和(目的2)评价DM1-BDS结合物治疗BC的疗效和解剖灵活性。 我们将单独评估DM1-BDS或与批准的免疫检查点抑制剂pembrolizumab联合使用 由食品和药物管理局提供，用于治疗NMIBC和MIBC。免疫分析将解决反- 肿瘤活动。这一信息将对显著改善治疗结果至关重要。使用附加的 我们还预计，我们的UDD方法将具有异常的转位能力，并可用于治疗其他 疾病(如膀胱炎)，只需将附加在多肽序列上的药物替换为 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.