Pre-clinical safety and efficacy evaluation of sodium chloride nanoparticles for treating non-muscle invasive bladder cancer.

person Andrew Gdowski The University of North Carolina at Chapel Hill, Chapel Hill, NC info_outline Andrew Gdowski, Lucia Kim, Xining Lai, Xinrui Ma, John Raupp, Shuyue Zhan, Wolfgang Beckabir, Michael Sturdivant, Sara Elizabeth Wobker, Zibo Li, Jin Xie, William Y. Kim

Authors person Andrew Gdowski The University of North Carolina at Chapel Hill, Chapel Hill, NC info_outline Andrew Gdowski, Lucia Kim, Xining Lai, Xinrui Ma, John Raupp, Shuyue Zhan, Wolfgang Beckabir, Michael Sturdivant, Sara Elizabeth Wobker, Zibo Li, Jin Xie, William Y. Kim Organizations The University of North Carolina at Chapel Hill, Chapel Hill, NC, Lineberger Comprehensive Cancer Center, Chapel Hill, NC, The University of Georgia, Athens, GA, University of Michigan, Ann Arbor, MI, Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, Department of Radiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC Abstract Disclosures Research Funding U.S. National Institutes of Health Background: Non-muscle invasive bladder cancer (NMIBC) presents a significant therapeutic challenge. Current treatment modalities such as BCG and intravesical chemotherapy given after transurethral resection of bladder tumors (TURBT), while effective, are associated with high cost burdens and are difficult for patients to tolerate due to side effects. This ultimately limits treatment regimen duration and decreases the effectiveness of the therapy which frequently leads to local recurrence. Sodium Chloride Nanoparticles (NaCl-NPs) have previously shown promise in preclinical models of intra-tumoral injection of various tumor types but has not been tested in more clinically relevant models of bladder cancer. In this study, we evaluate the safety and efficacy of NaCl-NPs as a local intravesical therapy for preventing tumor development in a preclinical murine model of bladder cancer. Methods: We conducted a dose escalation experiment via intravesical instillation of increasing doses of NaCl-NPs (300 ug/ml-2700 ug/ml, n=3 mice per group) to identify the maximum tolerated dose. Mice were treated on a weekly dosing schedule and toxicity was evaluated at day 35 as a composite of: evaluation of bladder histology with Hematoxylin and Eosin (H&E) staining by a board-certified pathologist, blood chemistry measurements, complete blood counts, as well as body weight measurement. Secondly, we assessed the efficacy of the nanoparticles through a tumor prevention experiment where MB49 bladder cancer cells were instilled in the murine bladder and shortly after treated with intravesical: 1.) Saline, 2.) Gemcitabine, or 3.) NaCl-NPs for 1 hour (n=18 per group). Mice were monitored for tumor development with 3D bladder ultrasound. In additional, overall survival (OS) was assessed. Results: The dose escalation study showed that there was no local or systemic toxicity in the NaCl-NP treated mice, even at the highest concentration (2700ug/ml). The tumor prevention study showed that mice treated with NaCl-NPs had a significant 2.55 fold reduction in tumors that developed at 4 weeks compared to saline (22% vs 56% respectively, p <0.05). This reduction was similar to that seen with intravesical gemcitabine, which is clinically, a standard of care intravesical chemotherapy. We also found an improvement in overall survival in the NaCl NP group with 70% of mice alive at 60 days compared to the other treatment groups (65% gemcitabine; 40% saline). Conclusions: Our findings suggest that NaCl-NPs could provide a safe and effective alternative therapy for preventing recurrence of NMIBC following transurethral resection of bladder tumors. This opens avenues for safer treatment protocols that can mitigate the side effects commonly seen in the management of early-stage bladder cancer.

Pre-clinical