Nanoscale Coordination Polymers Co-deliver Chemotherapeutics and siRNAs for Efficacious Treatment of Resistant Ovarian Cancer

纳米级配位聚合物共同提供化疗药物和 siRNA，有效治疗耐药性卵巢癌

• 批准号: 10329991
• 负责人: Wenbin Lin
• 金额: $ 41.57万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329991
• 关键词: Address; Biological; Biological Products; Blood Circulation; Cancer Etiology; Cancer Patient; Cancer cell line; Caring; Cations; Cause of Death; Cervical; Cessation of life; Charge; Cisplatin; Clinic; Deposition; Disease; Drug Kinetics; Drug resistance; Drug resistance pathway; ERBB2 gene; Endosomes; Exhibits; Formulation; Gene Silencing; Genes; Genetic Heterogeneity; High Pressure Liquid Chromatography; Immunoglobulin Fragments; In Vitro; Individual; Inductively Coupled Plasma Mass Spectrometry; Lipids; Malignant Neoplasms; Malignant neoplasm of ovary; Modeling; Molecular; Molecular Abnormality; Molecular Genetics; Multi-Drug Resistance; Multidrug Resistance Gene; Mus; Operative Surgical Procedures; Ovarian; Particle Size; Patients; Pharmaceutical Preparations; Platinum; Polymers; Proteins; Research; Resistance; Sampling; Signal Pathway; Small Interfering RNA; Structure; Surface; System; Terminal Disease; Testing; Therapeutic; Toxic effect; United States; Variant; Woman; anti-cancer; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinical translation; cytotoxicity; design; efficacious treatment; erbB-2 Receptor; fundamental research; gemcitabine; improved; in vivo; insight; mouse model; nanocarrier; nanomedicine; nanoparticle; nanoparticulate; nanoscale; nanotherapeutic; neoplastic cell; novel therapeutic intervention; particle; patient derived xenograft model; personalized medicine; preclinical study; rational design; refractory cancer; resistance mechanism; taxane; tumor; tumor heterogeneity; uptake

Project Summary: Ovarian cancer (OCa) is the fifth leading cause of cancer death for women in the United States. Intrinsically resistant and recurring ovarian cancers are a terminal disease that cannot be cured with existing therapeutics. Considering the molecular and genetic heterogeneity of tumors, we hypothesize that efficacious OCa therapy can be developed by determining the genetic abnormalities found in tumors of individual OCa patients and designing personalized therapy that can overcome patient-specific multi-drug resistance (MDR). We propose to develop robust nanoscale coordination polymers (NCPs) for the co-delivery of front-line and second-line OCa chemotherapeutics (cisplatin or cisplatin plus gemcitabine) and siRNA cocktails targeting MDR genes. A unique endosomal escape mechanism will be elucidated and is expected to be generally applicable to the rational design of nanocarriers for efficient delivery of biologics in vivo. This project will not only provide new fundamental insights nanomedicine research, but also holds great promise for clinical translation for the personalized treatment of resistant OCa. Aim 1: Develop NCP/siRNAs and evaluate their in vitro effects on resistant OCa cell lines. Two NCP/siRNAs formulations with chemotherapeutics in the core and siRNAs targeting MDR in the shell will be developed and characterized. The in vitro gene silencing and cytotoxicity will be evaluated in resistant OCa cells. Aim 2: Evaluate the anticancer efficacy of NCP/siRNAs in orthotopic mouse tumor models of resistant OCa. The general toxicity and anticancer efficacy of NCP/siRNAs will be assessed in mouse models. Aim 3: Actively target NCP/siRNAs by incorporating Her2/neu antibody fragments into the NCP/siRNAs shell. Small protein Her2/neu antibody fragments will be conjugated to a lipid and incorporated into the outer shell of NCP/siRNAs and the resulting nanoparticles will be tested in Her2/neu high expressing and Her2/neu low expressing resistant OCa tumor models to evaluate changes in pharmacokinetics, tumor deposition, and efficacy. Aim 4: Evaluate the anticancer efficacy of NCP/siRNAs and NCP/siRNAs/H2A in patient-derived xenograft (PDX) mouse models of resistant OCa. The expression of MDR-associated genes will be analyzed in OCa tumor PDX samples collected by the Mayo clinic. Personalized therapy will be designed entailing chemotherapeutic agent(s) and the choice of siRNAs targeting MDR genes. Confirmed platinum-resistant tumor cells will be used to evaluate the anticancer efficacy of NCP/siRNAs in orthotopic PDX OCa mouse models. Tumors from Her-2/neu receptor positive and negative patients will be further evaluated for anticancer efficacy by NCP/siRNAs/H2A. Through these aims we seek to establish a new paradigm for the treatment of resistant OCa. NCP/siRNAs can provide personalized therapy for OCa patients and achieve greatly enhanced anticancer efficacy in resistant OCa. As the standards of care for cervical and other cancers, cisplatin-based NCP/siRNAs can have broad impact on treating other resistant cancers.

项目概要： 卵巢癌 (OCa) 是美国女性癌症死亡的第五大原因。本质上 耐药性和复发性卵巢癌是一种无法用现有疗法治愈的绝症。 考虑到肿瘤的分子和遗传异质性，我们假设有效的 OCa 疗法 可以通过确定个体 OCa 患者肿瘤中发现的遗传异常来开发 设计可以克服患者特异性多药耐药性 (MDR) 的个性化治疗。我们建议 开发强大的纳米级配位聚合物 (NCP)，用于联合输送一线和二线 OCa 针对 MDR 基因的化疗药物（顺铂或顺铂加吉西他滨）和 siRNA 混合物。一个独特的 内体逃逸机制将被阐明，并有望普遍适用于合理设计 纳米载体在体内有效递送生物制剂。该项目不仅将提供新的基本见解 纳米医学研究，而且也为个性化治疗的临床转化带来了巨大的希望 抗OCa。 目标 1：开发 NCP/siRNA 并评估其对耐药 OCa 细胞系的体外效果。两个 NCP/siRNA 将开发核心为化疗药物、外壳为靶向 MDR 的 siRNA 的制剂， 特点。将在耐药 OCa 细胞中评估体外基因沉默和细胞毒性。 目标 2：评估 NCP/siRNA 在耐药 OCa 原位小鼠肿瘤模型中的抗癌功效。这 NCP/siRNA 的一般毒性和抗癌功效将在小鼠模型中进行评估。 目标 3：通过将 Her2/neu 抗体片段整合到 NCP/siRNA 外壳中，主动靶向 NCP/siRNA。 小蛋白质 Her2/neu 抗体片段将与脂质缀合并整合到 NCP/siRNA 和由此产生的纳米颗粒将在 Her2/neu 高表达和 Her2/neu 低表达中进行测试 表达耐药 OCa 肿瘤模型以评估药代动力学、肿瘤沉积和疗效的变化。 目标 4：评估 NCP/siRNA 和 NCP/siRNA/H2A 在患者来源的异种移植物 (PDX) 中的抗癌功效 抗性 OCa 小鼠模型。将在 OCa 肿瘤 PDX 中分析 MDR 相关基因的表达 梅奥诊所采集的样本。将设计包含化疗药物的个性化治疗 以及针对 MDR 基因的 siRNA 的选择。已确认的铂耐药肿瘤细胞将用于评估 NCP/siRNA 在原位 PDX OCa 小鼠模型中的抗癌功效。 Her-2/neu 受体肿瘤 阳性和阴性患者将通过NCP/siRNAs/H2A进一步评估抗癌功效。 通过这些目标，我们寻求建立治疗耐药性 OCa 的新范例。 NCP/siRNA 可以为OCa患者提供个性化治疗，并在耐药性中取得大幅增强的抗癌疗效 奥卡。作为宫颈癌和其他癌症的护理标准，基于顺铂的 NCP/siRNA 具有广泛的应用前景。 对治疗其他耐药癌症的影响。

项目成果

Supramolecular metal-based nanoparticles for drug delivery and cancer therapy.

• DOI: 10.1016/j.cbpa.2021.01.005
• 发表时间: 2021-04
• 期刊: Current opinion in chemical biology
• 影响因子: 7.8
• 作者: Jiang X;He C;Lin W
• 通讯作者: Lin W

Pharmacological ascorbate potentiates combination nanomedicines and reduces cancer cell stemness to prevent post-surgery recurrence and systemic metastasis.

药理学抗坏血酸可增强组合纳米药物的作用并减少癌细胞干性，以防止术后复发和全身转移。

• DOI: 10.1016/j.biomaterials.2023.122037
• 发表时间: 2023
• 期刊: Biomaterials
• 影响因子: 14
• 作者: Jiang,Xiaomin;Liu,Jianqiao;Mao,Jianming;Han,Wenbo;Fan,Yingjie;Luo,Taokun;Xia,Junjie;Lee,MortenJ;Lin,Wenbin
• 通讯作者: Lin,Wenbin

Tumor-Activatable Nanoparticles Target Low-Density Lipoprotein Receptor to Enhance Drug Delivery and Antitumor Efficacy.

• DOI: 10.1002/advs.202201614
• 发表时间: 2022-08
• 期刊: ADVANCED SCIENCE
• 影响因子: 15.1
• 作者: Jiang, Xiaomin;Han, Wenbo;Liu, Jianqiao;Mao, Jianming;Lee, Morten J.;Rodriguez, Megan;Li, Youyou;Luo, Taokun;Xu, Ziwan;Yang, Kaiting;Bissonnette, Marc;Weichselbaum, Ralph R.;Lin, Wenbin
• 通讯作者: Lin, Wenbin

Retraction Notice to: Nanoscale Metal-Organic Framework Mediates Radical Therapy to Enhance Cancer Immunotherapy.

撤回通知：纳米级金属有机框架介导根治性治疗以增强癌症免疫治疗。

• DOI: 10.1016/j.chempr.2023.02.003
• 发表时间: 2023
• 期刊: Chem
• 影响因子: 23.5
• 作者: Ni,Kaiyuan;Aung,Theint;Li,Shuyi;Fatuzzo,Nina;Liang,Xingjie;Lin,Wenbin
• 通讯作者: Lin,Wenbin

Two-Stage SN38 Release from a Core-Shell Nanoparticle Enhances Tumor Deposition and Antitumor Efficacy for Synergistic Combination with Immune Checkpoint Blockade.

• DOI: 10.1021/acsnano.2c09788
• 发表时间: 2022-12-27
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Jiang, Xiaomin;Lee, Morten;Xia, Junjie;Luo, Taokun;Liu, Jianqiao;Rodriguez, Megan;Lin, Wenbin
• 通讯作者: Lin, Wenbin