Development of a novel biodegradable inorganic nanoparticle therapeutic for cancer

点击翻译按钮获取中文摘要

Abstract Bladder cancer is the sixth most prevalent cancer malignancy. More than 80,000 new cases are diagnosed in the USA each year, among which 75% are non-muscle-invasive bladder cancer (NMIBC). High-risk NMIBC is often treated with intravesical instillation of Bacille Calmette-Guérin (BCG), a bacterial vaccine, following surgically removing major tumors. While generally considered well tolerated, local and systemic side effects are common with BCG and can lead to discontinuation of the therapy in up to 20% patients. Moreover, about 30% patients do not respond to BCG. These patients require radical cystectomy with urinary diversion or chemotherapy and radiation, both of which are associated with considerable morbidity. Furthermore, BCG is currently in great shortage due to limited production and an increasing global demand. There is an urgent need of new treatment options that afford high efficacy, can be manufactured easily, and are better tolerated by patients. Our objective is to develop a safe and effective intravesical therapy based on phospholipid coated sodium chloride nanoparticles (SCNPs). These nanoparticles can enter cells through endocytosis and degrade inside them to release large amounts of Na+ and Cl-. This entails an increase of intracellular osmolarity, which causes plasma membrane and mitochondrial membrane depolarization, leading to cell necrosis and apoptosis. It is hypothesized that SCNPs as an intravesical therapy can be applied to affected bladder to kill bladder cancer cells. After therapy, SCNPs are reduced to NaCl salt, which is safely excreted via urine or absorbed by the host. Meanwhile, because SCNPs induce immunogenic cell death, it is also expected that intravesical SCNPs can stimulate an anticancer immunity that helps prevent tumor recurrence and progression. In this project, we will test these hypotheses first in vitro and then in vivo with murine orthotopic tumor models. Affording unique cancer cell killing mechanisms and minimal side effects, SCNPs hold great potential in clinical translation as a novel treatment option for bladder cancer.