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

• 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
• 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

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.

项目总结 卵巢癌是女性癌症相关死亡的第五大常见原因，导致的死亡人数更多。 比女性生殖系统的任何其他癌症都要多。卵巢癌病死率高的主要原因 癌症是多药耐药的。由于传统抗癌药物不能在杀死耐药细胞的同时引起 恶化患者健康状况的全身毒性--一种新的有效而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的聚合物-金属组合，它独特地 诱导溶酶体铜升高，启动内源性细胞凋亡途径。因此，这种组合是 高度选择性地杀死癌细胞，包括耐药的卵巢癌细胞，而不是 破坏健康的细胞。本研究的目的是开发一种聚合物-金属纳米络合物(PMC)，用于 通过癌细胞选择性凋亡机制安全有效地治疗卵巢癌。我们的项目已经 三个具体目标。目的1，探讨PMC对肿瘤细胞的杀伤作用机制。目标2将确定 PMC的肿瘤选择性杀伤机制及其处方优化 癌细胞。目的3研究PMC的药代动力学性质，考察PMC的生物分布。 评价其对肿瘤生长的抑制作用、免疫反应和全身毒性。总而言之，唯一的 PMC的抗癌机制及其简单的处方将为临床医生提供安全有效的控制工具 有利于晚期卵巢癌和卵巢癌患者。