An urinary drug disposing approach for treatment of bladder Cancer

一种治疗膀胱癌的泌尿药物处置方法

基本信息

批准号：
10737090
负责人：
Benedict Shek Hang Law
金额：
$ 66.59万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-13 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10737090
关键词：
Affect Amino Acids Anatomy Animals Antibiotics Aspartic Acid BCG Live BCG Vaccine Bacillus Calmette-Guerin Therapy Behavior Biodistribution Biological Assay Biological Markers Bladder Bladder Neoplasm Bypass Cancer Patient Catheterization Catheters Charge Chemicals Combined Modality Therapy Data Deposition Diagnosis Disease Disease Management Doxorubicin Drug Carriers Drug Delivery Systems Drug Kinetics Excision Excretory function Goals Hospital Costs Human Immune Immune checkpoint inhibitor Immunocompetent Immunotherapy Implant Infection Infective cystitis Infusion procedures Intravenous Kidney Length Liver Malignant Neoplasms Malignant neoplasm of urinary bladder Microtubules Mitomycins Morbidity - disease rate Mus Operative Surgical Procedures Optics Organ Outcome Output Pain Patients Peptides Pharmaceutical Preparations Pharmacotherapy Procedures Property Quality of life Radical Cystectomy Recurrence Recurrent Malignant Neoplasm Recurrent disease Renal clearance function Residual Cancers Reticuloendothelial System Serine Spleen Surface Survival Rate Symptoms System Techniques Therapeutic Studies Time Toxic effect Transitional Cell Carcinoma Treatment Efficacy Treatment outcome Treatment-related toxicity United States Food and Drug Administration Urinary system Urinary tract Urine Urothelium X-Ray Computed Tomography absorption analog cancer cell cancer recurrence cancer therapy chemotherapy clinical translation combinatorial comparative compliance behavior cost design digital flexibility functional group high risk immune cell infiltrate improved improved outcome in vivo inhibitor interest intravesical minimally invasive mortality muscle invasive bladder cancer non-muscle invasive bladder cancer novel novel strategies pembrolizumab peptide analog precision drugs preclinical study preservation protein aminoacid sequence standard care survival outcome translational study treatment duration treatment response tumor tumor microenvironment uptake urinary

项目摘要

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.

项目摘要大多数膀胱癌（BC）患者在早期被诊断出。超过80％的案件是非穆斯特入侵BC（NMIBC）。标准治疗涉及通过手术切除肿瘤，然后进行静脉内免疫疗法，状态杆菌状态疗法（BCG）或静脉内化学疗法（ITC）用于放射性残留癌细胞。这涉及通过导管将BCG或药物溶液直接滴入膀胱。然而，癌症复发率仍然不可接受（50-80％）。另一方面，人们对保留不符合自由基膀胱切除术的肌肉侵入性BC（MIBC）的膀胱 ITC。 BCG和ITC有局限性。治疗是局部的。药物溶液无法到达位于肿瘤在上尿路中。药物给药后不久，患者通常需要空隙。导管插入手术是侵入性的，可能会导致感染和泌尿症状，导致患者不良遵守。目前，也缺少BCG。该项目的目的是开发一种方法应对卑诗省治疗的重要药物输送障碍，以改善治疗和生存结果。一个肽的快速肾脏清除率可能是将治疗引导到尿液系统（URS）可能是有利的。我们提议生物启动肽（BDD）以克服药物递送障碍。 BDD可以静脉注射而不是静脉内。证明使用BDD作为载体可以促进药物，例如默本汀（DM1）和阿霉素（DOX），仅通过肾脏清除率消除，如果无法检测到的话，主要器官的沉积。我们假设该平台被用作ITC的替代方案，将急切地提供所需的治疗方法更完整，有效。这种泌尿药处置的优势（UDD）系统包括：（1）在整个URS中连续的药物流动，（2）膀胱居住时间的延长（治疗持续时间）和（3）微创应用。如果成功，这种方法也将避免导管插入术，改善患者的生活质量并降低住院费用。我们的具体目标将重点临床前和翻译研究至：（目标1）研究所需的物理特性（包括 A的功能组，长度和表面电荷）和A的给药参数（输注率和体积）新开发的BDD类似物BDS，具有改进的UDD财产，可精确地将药物输送到URS；（AIM 2）评估DM1-BDS偶联物用于BC治疗的治疗效率和解剖柔韧性。我们将单独评估DM1-BDS，或与Pembrolizumab（一种批准的免疫切除剂抑制剂）结合由食品和药物管理局（Food and Drug Administration）治疗NMIBC和MIBC。免疫分析将解决肿瘤活动。该信息对于显着改善治疗结果至关重要。还有其他进步，我们还预见到我们的UDD方法将异常转座，可用于治疗其他方法疾病（例如，膀胱感染），仅通过用用抗生素。