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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的膀胱癌是第六大最常见的癌症恶性肿瘤，新诊断病例超过 80,000 例。每年在美国，其中75%是非肌层浸润性膀胱癌(NMIBC)，属于高危NMIBC。通常通过膀胱内滴注卡介苗（BCG）（一种细菌疫苗）进行治疗，然后手术切除主要肿瘤虽然通常被认为耐受性良好，但局部和全身副作用仍然存在。与 BCG 常见，可导致多达 20% 的患者停止治疗。患者对卡介苗没有反应这些患者需要进行尿流改道或根治性膀胱切除术。化疗和放疗均与相当大的发病率相关。由于产量有限和全球需求不断增加，目前严重短缺。提供高效、易于制造且耐受性更好的新治疗方案患者。我们的目标是开发一种基于磷脂涂层钠的安全有效的膀胱内治疗这些纳米颗粒可以通过胞吞作用进入细胞并在内部降解。它们释放大量的 Na+ 和 Cl-，这会导致细胞内渗透压增加。质膜和线粒体膜去极化，导致细胞坏死和凋亡。促进 SCNP 作为膀胱内治疗可应用于受影响的膀胱以杀死膀胱癌治疗后，SCNP 被还原为 NaCl 盐，通过尿液安全排出或被宿主吸收。同时，由于 SCNP 会诱导免疫原性细胞死亡，因此膀胱内 SCNP 也有望刺激抗癌免疫力，有助于防止肿瘤复发和进展。首先在体外测试这些假设，然后用小鼠原位肿瘤模型在体内测试这些假设。细胞杀伤机制和最小的副作用，SCNPs 作为一种新型药物在临床转化方面具有巨大的潜力膀胱癌的治疗选择。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

阻断谷氨酰胺依赖性细胞存活可增强 CPI-613 在头颈癌中的抗肿瘤功效。

DOI：
发表时间：
2021-12-14
期刊：
影响因子：
0
作者：
Lang, Liwei;Wang, Fang;Ding, Zhichun;Zhao, Xiangdong;Loveless, Reid;Xie, Jin;Shay, Chloe;Qiu, Peng;Ke, Yonggang;Saba, Nabil F;Teng, Yong
通讯作者：
Teng, Yong