Sodium Chloride Nanoparticle as a Therapeutic for Bladder Cancer

Bladder cancer is the sixth most common cancer type in the US and the tenth most common cause of cancer-related death. Depending on whether the tumor has invaded the muscularis propria, bladder cancer can be classified into two broad categories, which are non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). About 75% of newly diagnosed cases are NMIBC. Surgical transurethral resection of bladder tumor (TURBT) is the standard treatment for NMIBC but recurrence rates are high. To prevent tumor recurrence and progression, TURBT is often followed by intravesical chemotherapy or immunotherapy with Bacillus Calmette–Guérin (BCG). However, about 30% of the patients are not responsive to BCG and chemotherapy as a second-line treatment is not effective. We investigated sodium chloride nanoparticles (SCNPs) as a novel adjuvant therapy for NMIBC. SCNPs are expected to be delivered into the bladder through a urethral catheter for effective killing of cancer cells. After treatment, SCNPs will degrade into constituent ions, which are safely excreted in the urine.<br/>The project is based on the hypothesis that SCNPs can break the osmotic balance across the plasma membrane of cancer cells. Ion homeostasis is essential for maintaining the integrity of the plasm membrane and sustaining the normal cell functions. Breaking the homeostasis could disrupt the potential balance and interrupt essential cellular processes. Instead of using organic ionophores, we explore SCNPs as a new strategy to carry ions across the plama membrane, eventually causing cancer cell death. While the plasma membrane is not permeable to ions, we hypothesize that SCNPs can enter the cell through endocytosis and degrade inside cells, releasing large quantities of ions into cancer cells therein.<br/>Our extensive <i>in vitro</i> studies strongly support the hypothesis. Moreover, our results showed that SCNPs are more toxic to cancer cells than normal cells. This is because cancer cells have higher intracellular sodium levels, making them more susceptible to SCNPs-induced ion disruption. We have tested SCNPs <i>in vivo</i> in tumor models established with UPPL-1541 and other bladder cancer cell lines. Our data confirmed that SCNPs can effectively suppress tumor growth without causing additional systemic toxicity. Last but not least, we observed that cancer cells succumbed to SCNPs released immunogenic cell death (ICD) signals including HMGB1, ATP, and CRT. Preliminary studies indicate that combination therapy with SCNPs and anti-PD-1 antibodies can trigger anti-cancer immune response, which contributes to inhibited tumor growth and metastasis.