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 7ligands (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.
|Chao, Ying; Karmali, Priya P; Mukthavaram, Rajesh et al. (2013) Direct recognition of superparamagnetic nanocrystals by macrophage scavenger receptor SR-AI. ACS Nano 7:4289-98|