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Photo-assisted targeting of immunotherapy to the bladder

光辅助膀胱免疫治疗靶向

基本信息

批准号：
8769752
负责人：
Tomoko Hayashi
金额：
$ 16.31万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8769752
关键词：
Accounting Agonist Animal Model Animals Area Binding Bladder Bladder Neoplasm Calmette-Guerin Bacillus Cancer Center Cancer Model Cancer Patient Cells Chemistry Chronic Clinical Clinical Trials Common Neoplasm Computers Consult Development Dose Drug Delivery Systems Drug Formulations Encapsulated Engineering Environment Excision Extracellular Matrix Fiber Optics Glues Goals Immune Immune response Immunization Immunology Immunotherapy In Vitro Infection Inflammation Inflammatory Response Laboratories Lead Life Ligand Binding Ligands Lipids Liposomes Malignant Neoplasms Malignant neoplasm of urinary bladder Measurable Mechanics Micelles Modality Outcome Patients Peptides Permeability Photochemistry Principal Investigator Quality of Care Residual Tumors Scheme Solutions Specific qualifier value Surface System Testing Therapeutic Time To specify Ultraviolet Rays Urethra Urologic Cancer Urology Urothelium arginyllysine cancer therapy cysteinylglycine human TLR7 protein improved in vivo innovation intravesical mouse model nanoparticle neoplastic cell novel novel strategies outcome forecast particle pathogen professor research study residence standard care success targeted delivery tumor uptake urologic

项目摘要

DESCRIPTION (provided by applicant): Bladder cancer is the fifth most common tumor in the USA, accounting for 5-10% of all malignancies. The standard treatment is the trans-urethral resection of the tumor, followed by intravesical immunotherapy (Bacillus Calmette-Guerin (BCG)). BCG causes long-term immune inflammation that eradicates residual tumor cells. Despite its efficacy, BCG is a living pathogen that causes infections and complications in a large number of patients. Therefore, novel alternative approaches to the living pathogen therapy are constantly being explored. In the Carson laboratory, formulations of synthetic Toll-like receptor 7 ligands (TLR7) were found to be potent inducers of inflammation in the bladder, mimicking BCG treatment without resulting in any of the problems commonly caused to BCG. Intravesical TLR7 ligands showed efficacy in mouse models of bladder cancer and are currently in clinical trials. However, the binding and retention of the TLR7 ligands formulations in the harsh bladder environment is not very efficient, which requires chronic dosing for maintaining chronic inflammation and improving the therapeutic outcome. We propose a novel solution to prolonged delivery of TLR-7 ligands in the bladder. At the Moores UCSD Cancer Center, we found peptides that efficiently penetrated the urothelium following local mechanical damage to the urothelium (similar to the damage following tumor removal). We hypothesize that targeting TLR7 ligand in nanoparticles using the above peptide can increase the delivery and promote more potent inflammation than free molecules. As an additional step, photochemistry will be used in order to stably "glue" the particles to the bladder wall; photocrosslinking could prolong the residence time of the TLR-7-containing nanoparticles in the bladder and therefore prolong immune inflammation. This exploratory project will focus on the proof-of-concept of targeting and photochemistry in the bladder, whereas the main measurable outcome will be the level of the TLR-7 agonist delivery, time of residence in the bladder, and the duration of the immune inflammation in vivo. We will: (1) Prepare and characterize photoactive nanoparticles for targeted delivery of TLR7 ligands; (2) Test cell binding and immunostimulation in vitro; (3) Perform photocrosslinking experiments in vivo and quantify the TLR7 ligand delivery and inflammatory response in vivo. The successful accomplishment of the goals will allow us to perform full-scale tumor-treatment studies, large animal studies, and to explore the delivery of additional therapeutic modalities using a targeting-photocrosslinking scheme. The development of delivery vehicles that bind to the areas of urothelial damage, and then chemically attach in the specified areas for an extended period of time, is a novel type of controlled drug delivery in the bladder that can dramatically improve quality of care for urological patients.

描述（由申请人提供）：膀胱癌是美国第五大常见肿瘤，占所有恶性肿瘤的 5-10%。标准治疗是经尿道肿瘤切除术，然后进行膀胱内免疫治疗（卡介苗（BCG））。卡介苗会引起长期免疫炎症，从而消除残留的肿瘤细胞。尽管卡介苗具有功效，但它是一种活病原体，会导致大量患者感染和并发症。因此，人们不断探索活病原体治疗的新替代方法。在 Carson 实验室，合成 Toll 样受体 7 的制剂配体（TLR7）被发现是膀胱炎症的有效诱导剂，模仿 BCG 治疗，但不会导致 BCG 常见的任何问题。膀胱内 TLR7 配体在小鼠膀胱癌模型中显示出疗效，目前正在进行临床试验。然而，TLR7配体制剂在恶劣的膀胱环境中的结合和保留不是很有效，这需要长期给药以维持慢性炎症并改善治疗结果。我们提出了一种新的解决方案来延长 TLR-7 配体在膀胱中的递送。在加州大学圣地亚哥分校摩尔斯癌症中心，我们发现在尿路上皮局部机械损伤（类似于肿瘤切除后的损伤）后，肽可以有效地渗透尿路上皮。我们假设使用上述肽靶向纳米颗粒中的 TLR7 配体可以增加递送并促进比游离分子更有效的炎症。作为附加步骤，将使用光化学将颗粒稳定地“粘合”到膀胱壁上；光交联可以延长含有 TLR-7 的纳米颗粒在膀胱中的停留时间，从而延长免疫炎症。该探索性项目将重点关注膀胱中靶向和光化学的概念验证，而主要可测量结果将是 TLR-7 激动剂的递送水平、在膀胱中的停留时间以及体内免疫炎症的持续时间。我们将：（1）制备并表征用于 TLR7 配体靶向递送的光活性纳米颗粒；（2）体外测试细胞结合和免疫刺激； (3)进行体内光交联实验并量化体内TLR7配体递送和炎症反应。这些目标的成功实现将使我们能够进行全面的肿瘤治疗研究、大型动物研究，并探索使用靶向光交联方案提供其他治疗方式。递送载体的开发与尿路上皮损伤区域结合，然后在较长时间内以化学方式附着在指定区域，是一种新型的膀胱内受控药物递送，可以显着提高泌尿科患者的护理质量。