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：
10680585
负责人：
Peisheng Xu
金额：
$ 33.17万
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/10680585
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 Deterioration 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 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 cancer cell cancer drug resistance 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 novel therapeutic intervention ovarian neoplasm public health relevance response siRNA delivery success systemic toxicity tool 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.

项目摘要卵巢癌是女性与癌症相关死亡的第五大最常见原因，并导致更多死亡比女性生殖系统的任何其他癌症。卵巢高死亡率高的主要原因癌症是多药的抗性。由于常规抗癌药物不能杀死耐药细胞，同时导致对恶化患者健康状况恶化的全身毒性，这是一种新型的卵巢癌有效治疗迫切需要。我们的初步研究发现了一种新颖的聚合物金属组合诱导溶酶体铜升高引发了内在凋亡途径。因此，这种组合是高度选择性地杀死癌细胞，包括耐药性卵巢癌细胞，而不是破坏健康细胞。这项研究的目的是开发用于聚合物 - 金属纳米复合物（PMC）通过癌细胞选择性凋亡机制安全有效的卵巢癌疗法。我们的项目有三个具体目标。在AIM 1中，我们将确定PMC癌细胞杀死作用的机制。 AIM 2将确定 PMC的癌症选择性杀戮机制并优化其配方，以达到最高的选择性癌细胞。 AIM 3将研究药代动力学特性，检查PMC的生物分布和评估其肿瘤生长抑制作用，免疫反应和全身毒性。总而言之 PMC及其简单配方的抗癌机制将为临床医生提供一个安全有效的控制工具晚期卵巢癌并受益于卵巢癌患者。