Development of a novel biodegradable inorganic nanoparticle therapeutic for cancer

开发一种新型可生物降解的无机纳米颗粒治疗癌症

• 批准号: 10651626
• 负责人: WILLIAM Y. KIM
• 金额: $ 52.59万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651626
• 关键词: Ablation; Affect; Aftercare; Apoptosis; BCG Live; BCG Vaccine; Bacterial Vaccines; Biocompatible Coated Materials; Bladder; Bladder Neoplasm; Cancer Patient; Cancer cell line; Categories; Cell membrane; Cells; Cellular Metabolic Process; Chemotherapy and/or radiation; Development; Diagnosis; Dose; Electrolytes; Endocytosis; Epirubicin; Excretory function; Formulation; Goals; HMGB1 gene; Human; Immune checkpoint inhibitor; Immune system; Immunity; Immunocompetent; In Vitro; Intravesical Instillation; Ions; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of liver; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Measures; Mitochondria; Mitomycins; Modeling; Morbidity - disease rate; Mus; Muscle; Necrosis; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Osmolalities; Osmolar Concentration; Osmotic Shocks; Oxidative Stress; Patients; Phospholipids; Production; Prognosis; Progression-Free Survivals; Property; Quality of life; Radical Cystectomy; Recommendation; Recurrent tumor; Resistance; Salts; Scheme; Skin Cancer; Sodium; Sodium Chloride; Swelling; Testing; Therapeutic; Toxic effect; Transurethral Resection; Treatment Efficacy; Tumor Immunity; Urethra; Urinary Diversion; Urination; Urine; Urothelial Cell; Water; Xenograft Model; absorption; anti-cancer; appropriate dose; cancer cell; cancer diagnosis; cancer type; cell killing; clinical translation; cytochrome c; cytotoxicity; gemcitabine; high risk; immunogenic cell death; in vivo; intravesical; malignant breast neoplasm; manufacture; mitochondrial membrane; nanomedicine; nanoparticle; neoplastic cell; non-muscle invasive bladder cancer; novel; particle; prevent; side effect; systemic toxicity; therapeutic nanoparticles; tumor

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.

抽象的 膀胱癌是第六大癌症恶性肿瘤。诊断出80,000多个新病例 在美国，每年，其中75％是非肌肉侵入性膀胱癌（NMIBC）。高危NMIBC是 经常用静脉内滴注巴奇氏菌Calteette-guérin（BCG），一个细菌阴道，随后 手术切除主要肿瘤。虽然通常认为耐受性良好，但本地和全身副作用是 BCG常见，可导致多达20％的患者中断治疗。此外，大约30％ 患者对BCG不反应。这些患者需要尿液转移或 化学疗法和放射线，两者都与考虑的发病率有关。此外，BCG是 目前由于产量有限和全球需求不断增长，目前处于极大的短缺。迫切需要 可以轻松制造高效率的新的治疗选择，并且可以更好地容忍 患者。 我们的目标是基于磷脂涂层钠开发安全有效的静脉治疗 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 他们释放大量的Na+和Cl-。这需要增加细胞内渗透气，这会导致 质膜和线粒体膜去极化，导致细胞坏死和凋亡。这是 假设SCNP作为静脉疗法可以应用于受影响的膀胱以杀死Blader Cancer 细胞。治疗后，将SCNP还原为NaCl盐，该盐可以通过尿液安全地超过或被宿主吸收。 同时，由于SCNP诱导免疫原性细胞死亡，因此也可以预期 刺激有助于防止肿瘤复发和进展的抗癌免疫力。在这个项目中，我们将 首先在体外测试这些假设，然后在体内与鼠矫形肿瘤模型进行体内。提供独特的癌症 细胞杀死机制和最小的副作用，SCNP在临床翻译中具有很大的潜力 膀胱癌的治疗选择。

项目成果

Blockade of glutamine-dependent cell survival augments antitumor efficacy of CPI-613 in head and neck cancer.

• DOI: 10.1186/s13046-021-02207-y
• 发表时间: 2021-12-14
• 期刊: Journal of experimental & clinical cancer research : CR
• 作者: Lang L;Wang F;Ding Z;Zhao X;Loveless R;Xie J;Shay C;Qiu P;Ke Y;Saba NF;Teng Y
• 通讯作者: Teng Y