Photo-assisted targeting of immunotherapy to the bladder

光辅助膀胱免疫治疗靶向

• 批准号: 8450071
• 负责人: Tomoko Hayashi
• 金额: $ 2.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450071
• 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

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肿瘤，占所有恶性肿瘤的5-10％。标准治疗方法是肿瘤的尿道切除术，然后进行静脉内免疫疗法（杆菌Calmette-guerin（BCG））。 BCG引起长期免疫炎症，消除残留的肿瘤细胞。尽管具有功效，但BCG还是一种活的病原体，会引起大量患者的感染和并发症。因此，正在不断探索新型的生活病原体疗法的替代方法。在Carson实验室中，合成Toll样受体7的制剂7 发现配体（TLR7）是膀胱中炎症的有效诱导剂，模仿BCG治疗而不会导致BCG造成的任何问题。静脉内TLR7配体在膀胱癌小鼠模型中显示出疗效，目前正在临床试验中。但是，TLR7配方在苛刻的膀胱环境中的结合和保留效率不是很高，这需要慢性剂量来维持慢性炎症并改善治疗结果。我们提出了一种新颖的解决方案，以延长膀胱中TLR-7配体的递送。在Moores UCSD癌症中心，我们发现肽在局部机械损伤对尿路上皮的损伤后有效地穿透了尿路上皮（类似于肿瘤切除后的损伤）。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多的有效炎症。作为另一个步骤，将使用光化学来稳定地将颗粒“胶合”到膀胱壁上。光叠链链接可以延长膀胱中含TLR-7的纳米颗粒的停留时间，从而延长免疫炎症。该探索性项目将重点放在膀胱中靶向和光化学的概念概念上，而主要的可测量结果将是TLR-7激动剂输送，膀胱居住时间的水平以及体内免疫炎症的持续时间。我们将：（1）准备并表征光活性纳米颗粒，以靶向TLR7配体的靶向递送； （2）在体外测试细胞结合和免疫刺激； （3）在体内执行光链接实验，并在体内量化TLR7配体递送和炎症反应。目标的成功实现将使我们能够使用靶向变态方案进行全面的肿瘤治疗研究，大型动物研究，并探索额外的治疗方式。与尿路上皮损伤区域结合并在特定区域进行化学附着的递送车的发展是一种新型的膀胱中受控药物输送类型，可以显着提高泌尿外科患者的护理质量。