Cancer cell selective killing nanoparticle for advanced ovarian cancer treatment

癌细胞选择性杀伤纳米颗粒用于晚期卵巢癌治疗

基本信息

批准号：
10453919
负责人：
Peisheng Xu
金额：
$ 33.85万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-09 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10453919
关键词：
Affect Antineoplastic Agents Apoptosis Area Under Curve Autophagocytosis BCL2 gene Biodistribution CASP9 gene Cancer Etiology Cancer Patient Cells Cessation of life Chemistry Chemoresistance Chemotherapy-Oncologic Procedure Cisplatin Clinical Clinical Trials Complex Control Groups Copper Data Death Rate Degradation Pathway Development Diagnosis Disease Dose Drug Kinetics Drug resistance Endocytosis Flow Cytometry Formulation Galactose Half-Life Head and Neck Cancer Health Histologic Immune Immune response Ions Lead Ligands Lysosomes Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Malignant neoplasm of prostate Maximum Tolerated Dose Mediating Membrane Potentials Metabolic Metals Methods Modeling Multi-Drug Resistance Neoplasm Metastasis Normal Cell Operative Surgical Procedures Oxidation-Reduction Pathway interactions Patients Permeability Pharmaceutical Preparations Polymers Process Property Protein Family Quality of life Relapse Research Resistance Risk Serum Survival Rate Tumor Debulking United States Woman anti-cancer base cancer cell cancer therapy cancer type cell killing cytochrome c density ethylene glycol female reproductive system galactose receptor human tissue improved in vivo intraperitoneal malignant breast neoplasm mitochondrial membrane mortality mouse model multicatalytic endopeptidase complex nanocomplexes nanoparticle novel ovarian neoplasm public health relevance response siRNA delivery success systemic toxicity tool treatment strategy tumor tumor growth

项目摘要

PROJECT SUMMARY Ovarian cancer is the fifth most common cause of cancer-related deaths in women and results in more deaths than any other cancer of the female reproductive system. The primary reason for the high death rate of ovarian cancer is multidrug-resistance. Since conventional anticancer drugs cannot kill drug-resistant cells while causing systemic toxicity to deteriorate patient health condition, a novel effective and safe treatment for ovarian cancer is urgently needed. Our preliminary study has discovered a novel polymer-metal combination which uniquely induces a lysosomal copper elevation initiated intrinsic apoptosis pathway. Consequently, this combination is highly selectively in killing cancer cells, including drug-resistant ovarian cancer cells, while not damaging healthy cells. The objective of this research is to develop a polymer-metal nano-complex (PMC) for safe and effective ovarian cancer therapy through a cancer cell selective apoptosis mechanism. Our project has three specific aims. In Aim 1, we will identify the mechanism of cancer cell killing effect of PMC. Aim 2 will identify the cancer selective killing mechanism of PMC and optimize its formulation to achieve the highest selectivity for cancer cells. Aim 3 will investigate the pharmacokinetic properties, examine the biodistribution of PMC, and evaluate its tumor growth inhibitory effect, immune response, and systemic toxicity. In summary, the unique anticancer mechanism of PMC and its simple formulation will provide clinicians a safe and effective tool to control advanced ovarian cancer and benefit ovarian cancer patients.

项目概要卵巢癌是女性癌症相关死亡的第五大常见原因，并导致更多死亡高于女性生殖系统的任何其他癌症。卵巢癌死亡率高的主要原因癌症具有多重耐药性。由于传统的抗癌药物无法杀死耐药细胞，同时会导致全身毒性会恶化患者的健康状况，这是一种新颖有效且安全的卵巢癌治疗方法是迫切需要的。我们的初步研究发现了一种新型聚合物-金属组合，其独特之处在于诱导溶酶体铜升高启动内在的细胞凋亡途径。因此，这个组合是高度选择性地杀死癌细胞，包括耐药性卵巢癌细胞，而不是损害健康细胞。本研究的目的是开发一种聚合物-金属纳米复合物（PMC）通过癌细胞选择性凋亡机制安全有效地治疗卵巢癌。我们的项目有三个具体目标。在目标1中，我们将确定PMC杀伤癌细胞作用的机制。目标 2 将确定研究PMC的癌症选择性杀伤机制并优化其配方以达到最高的选择性癌细胞。目标 3 将研究药代动力学特性，检查 PMC 的生物分布，以及评估其肿瘤生长抑制作用、免疫反应和全身毒性。总结来说，独特的 PMC的抗癌机制及其简单的配方将为临床医生提供安全有效的控制工具晚期卵巢癌，造福卵巢癌患者。