Photo-assisted targeting of immunotherapy to the bladder

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%。标准治疗是经尿道切除肿瘤，然后进行膀胱内免疫治疗（卡介苗（BCG））。BCG引起长期免疫炎症，根除残留的肿瘤细胞。尽管BCG有效，但它是一种活病原体，会导致大量患者感染和并发症。因此，不断探索活病原体治疗的新的替代方法。在卡森实验室，合成的Toll样受体7 配体（TLR 7）被发现是膀胱中炎症的有效诱导物，模拟BCG治疗而不导致通常由BCG引起的任何问题。膀胱内TLR 7配体在膀胱癌小鼠模型中显示出有效性，目前正在进行临床试验。然而，TLR 7配体制剂在苛刻的膀胱环境中的结合和保留不是非常有效，这需要长期给药以维持慢性炎症和改善治疗结果。我们提出了一种新的解决方案，以延长TLR-7配体在膀胱中的递送。在Moores UCSD癌症中心，我们发现了在对尿道的局部机械损伤（类似于肿瘤切除后的损伤）后有效穿透尿道的肽。我们假设使用上述肽靶向纳米颗粒中的TLR 7配体可以增加递送并促进比游离分子更有效的炎症。作为额外的步骤，将使用光化学以稳定地将颗粒“胶合”到膀胱壁;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。该探索性项目将专注于膀胱中靶向和光化学的概念验证，而主要可测量的结果将是TLR-7激动剂递送的水平，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）制备并表征用于靶向递送TLR 7配体的光活性纳米颗粒;（2）体外测试细胞结合和免疫刺激;（3）体内进行光交联实验并量化TLR 7配体递送和体内炎症反应。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。结合到尿路上皮损伤区域，然后在指定区域化学附着一段时间的递送载体的开发是一种新型的膀胱受控药物递送，可以显着提高泌尿外科患者的护理质量。 膀胱癌是美国第五大常见肿瘤，占所有恶性肿瘤的5-10%。我们建议探索一种新的方法来治疗膀胱癌，涉及紫外线稳定的“胶水”的治疗物质的膀胱。这种方法可以显着提高泌尿系统癌症患者的治疗效率和预后。

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. PUBLIC HEALTH RELEVANCE: Bladder cancer is the fifth most common tumor in the USA, accounting for 5-10% of all malignancies. We propose to explore a novel approach to therapy of the bladder cancer that involves ultraviolet light to stably "glue" the therapeutic substances to the bladder. This approach can dramatically improve treatment efficiency and prognosis for urological cancer patients.