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.

项目摘要 卵巢癌是女性癌症相关死亡的第五大常见原因， 比其他女性生殖系统的癌症都多卵巢癌死亡率高的主要原因 癌症是多药耐药性的。由于传统的抗癌药物不能杀死耐药细胞， 全身毒性恶化患者健康状况，一种有效和安全的卵巢癌新疗法 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， 诱导溶酶体铜升高启动内在凋亡途径。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。目的1：研究PMC对肿瘤细胞的杀伤作用机制。目标2将确定 PMC的选择性杀癌机制，并优化其配方，以达到最高的选择性， 癌细胞目的3将研究药代动力学特性，检查PMC的生物分布， 评价其肿瘤生长抑制作用、免疫应答和全身毒性。总之，独特的 PMC的抗癌机制和其简单的配方将为临床医生提供一个安全有效的工具，以控制 对晚期卵巢癌患者有益。