Development of a novel biodegradable inorganic nanoparticle therapeutic for cancer

摘要 膀胱癌是第六大最常见的恶性肿瘤。确诊的新病例超过8万例 在美国，每年有75%的非肌肉浸润性膀胱癌(NMIBC)。高风险的NMIBC是 通常采用卡介苗(BCG)膀胱内注射，一种细菌疫苗， 通过外科手术切除主要肿瘤。虽然普遍认为耐受性良好，但局部和系统性副作用是 与卡介苗一样常见，可导致高达20%的患者停止治疗。此外，约30% 患者对卡介苗没有反应。这些患者需要根治性膀胱切除尿流改道或 化疗和放射治疗，两者都与相当大的发病率有关。此外，卡介苗是 由于产量有限和全球需求增加，目前正处于严重短缺状态。有一个迫切的需要 一系列新的治疗方案，提供高疗效，易于制造，并更好地耐受性 病人。 我们的目标是开发一种安全有效的基于磷脂包埋钠的膀胱内治疗方法 氯化物纳米颗粒(SCNPs)。这些纳米颗粒可以通过内吞作用进入细胞，并在细胞内降解。 它们释放出大量的Na+和Cl-。这会导致细胞内渗透压的增加，从而导致 质膜和线粒体膜去极化，导致细胞坏死和凋亡。它是 假设SCNPs作为一种膀胱内治疗方法可以应用于受影响的膀胱以杀死膀胱癌 细胞。治疗后，SCNPs被还原为氯化钠盐，可以安全地通过尿液排泄或被宿主吸收。 同时，由于SCNPs可以诱导免疫原性细胞死亡，因此也可以预期SCNPs膀胱内可以 激发抗癌免疫力，帮助防止肿瘤复发和进展。在这个项目中，我们将 首先在体外验证这些假说，然后在体内用小鼠原位肿瘤模型进行验证。患上独特的癌症 细胞杀伤机制和最小的副作用，SCNPs作为一种小说在临床翻译中具有巨大的潜力 膀胱癌的治疗选择。

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.