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。新增确诊病例超8万例 在美国，每年有75%的膀胱癌是非肌层浸润性膀胱癌（NMIBC）。高风险NMIBC是 通常通过膀胱内滴注卡介苗（BCG，一种细菌疫苗）治疗， 手术切除大肿瘤虽然一般认为耐受性良好，但局部和全身副作用是 常见于BCG，可导致高达20%的患者停止治疗。此外，约30% 患者对BCG无反应。这些患者需要根治性膀胱切除术伴尿流改道， 化疗和放疗，这两者都与相当大的发病率有关。此外，BCG是 目前由于产量有限和全球需求不断增加，迫切需要 新的治疗选择，提供高效率，可以很容易地制造，并更好地耐受 患者 我们的目标是开发一种安全有效的基于磷脂包被钠的膀胱内治疗方法 氯化物纳米颗粒（SCNP）。这些纳米颗粒可以通过内吞作用进入细胞，并在内部降解 它们释放大量的Na+和Cl-。这需要细胞内渗透压的增加， 质膜和线粒体膜去极化，导致细胞坏死和凋亡。是 假设SCNP作为膀胱内治疗可应用于受影响的膀胱以杀死膀胱癌 细胞治疗后，SCNP被还原为NaCl盐，可通过尿液安全排出或被宿主吸收。 同时，由于SCNP诱导免疫原性细胞死亡，还预期膀胱内SCNP可 刺激抗癌免疫力，有助于防止肿瘤复发和进展。在这个项目中，我们将 首先在体外然后在体内用鼠原位肿瘤模型检验这些假设。提供独特的癌症 细胞杀伤机制和最小的副作用，SCNPs作为一种新的临床翻译具有巨大的潜力， 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.