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.

项目概要大多数膀胱癌 (BC) 患者在早期就被诊断出来，其中 80% 以上的病例属于非肌肉癌。侵入性 BC（NMIBC）的标准治疗包括手术切除肿瘤，然后进行膀胱内灌注。免疫疗法、卡介苗 (BCG) 或膀胱内化疗 (ITC) 以根除残留这涉及通过导管将卡介苗或药物溶液直接注入膀胱。另一方面，癌症复发率仍然高得令人无法接受（50-80%）。保留不适合根治性膀胱切除术的肌层浸润性 BC (MIBC) 患者的膀胱 ITC 和 ITC 的治疗方法都是局部的。在上尿路，患者通常需要在给药后不久排尿。该过程是侵入性的，可能会导致感染和泌尿系统症状，从而导致患者状况不佳目前，BCG 还存在不足，该项目的目标是开发一种方法来满足合规性。克服 BC 疗法的重大药物输送障碍，以改善治疗和生存结果 A。肽的快速肾清除率有利于泌尿系统 (URS) 的治疗。提出一种生物惰性肽（Bdd）来克服药物输送障碍，Bdd 可以静脉注射而不是注射。与膀胱内注射相比，Bdd 作为载体的使用被证明可以促进药物，例如美坦辛 (DM1) 和阿霉素（DOX），完全通过肾脏清除，具有最小的（如果不是无法检测到的话）我们希望这个平台作为 ITC 的替代品，能够提供紧急的解决方案。这种尿毒处置（UDD）的优点是需要更彻底和有效的治疗。系统包括：(1) 整个 URS 中的连续药物流动，(2) 膀胱停留时间的延长（治疗持续时间），以及（3）微创应用如果成功，这种方法也将避免。我们的具体目标将集中于导管插入术、改善患者的生活质量和降低住院费用。临床前和转化研究旨在：（目标 1）研究所需的理化特性（包括功能组、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 特性，用于将药物精确输送到 URS；（目标 2）评估 DM1-Bds 缀合物用于 BC 治疗的治疗效果和解剖灵活性。我们将单独评估 DM1-Bds 或与派姆单抗（一种已批准的免疫检查点抑制剂）联合使用由美国食品和药物管理局批准，用于治疗 NMIBC 和 MIBC 的免疫分析将解决抗-MIBC 问题。这些信息对于显着改善治疗效果至关重要。随着进步，我们还预见到我们的 UDD 方法将具有非凡的可移植性，并且可用于治疗其他人疾病（例如膀胱感染），只需用以下药物替换肽序列上的药物即可抗生素。