Integrated Nano-Therapeutics to Overcome Tumor Plasticity and Resistance

综合纳米疗法克服肿瘤可塑性和耐药性

• 批准号: 9165227
• 负责人: Mansoor M Amiji
• 金额: $ 29.99万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2018-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9165227
• 关键词: A549; Acute; Address; Affect; Biodistribution; Biological Assay; Blood Cell Count; Body Weight; CD44 gene; Cancer Etiology; Cancer Patient; Cell Survival; Cessation of life; Charge; Cisplatin; Clinical; Clinical Treatment; Collaborations; Complement Activation; Custom; Development; Drug Kinetics; Drug resistance; Encapsulated; Engineering; Enzymes; Epidermal Growth Factor Receptor; Epigenetic Process; Formulation; Genetic; Goals; Guidelines; Histopathology; Hyaluronic Acid; In Vitro; Inflammatory Response; Libraries; Link; Liver; Luciferases; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; MicroRNAs; Mitochondria; Modeling; Morphology; Multi-Drug Resistance; Mutation; Nanotechnology; Non-Small-Cell Lung Carcinoma; Nuclear; Nucleic Acids; Paclitaxel; Pathway interactions; Peptides; Performance; Phenotype; Refractory; Refractory Disease; Research; Resistance; SKOV3 cells; Safety; Solid Neoplasm; Specificity; Sulfhydryl Compounds; System; Techniques; Therapeutic; Tissues; Transfection; Translating; Treatment Efficacy; Treatment Failure; Validation; Woman; Work; Xenograft Model; aqueous; base; cancer cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinically significant; epigenetic marker; improved; in vitro Model; in vivo; innovation; men; mortality; nano; nanoparticle; nanotherapeutic; neoplastic cell; novel; self assembly; targeted delivery; tool; transgene expression; treatment response; tumor; tumor microenvironment; tumor xenograft

PROJECT SUMMARY Tumor plasticity and the development of multidrug resistance (MDR) remain the most important challenge in clinical cancer therapy, especially in non-small cell lung cancer (NSCLC) and ovarian cancer (OC). We hypothesize that phenotypic and epigenetic genetic reprogramming of tumor cells in NSCLC and OC would significantly improve the therapeutic response, especially in refractory disease. The main objective of the NCI's Innovative Research in Cancer Nanotechnology (IRCN) (PAR-14-285) application is to develop and evaluate an innovative microRNA (miR)-based phenotypic and epigenetic cellular reprogramming approach using a highly versatile dual-targeted hyaluronic acid (HA)-based nanoplatform to eradicate acquired MDR. This objective is consistent with the IRCN guideline for possible research direction in developing “techniques and tools to overcome failure of therapy”. Our preliminary results show that dual EGFR/CD44-targeted HA nanoparticles loaded with miR-34a expressing mimics were effective in transgene expression, altered nuclear and mitochondrial epigenetic markers in A549 wild-type and A549DDP cisplatin-resistant NSCLC models in vitro and in vivo. The specific aims of the application are as follows: (1) “Click” synthesis of HA-based functional blocks and efficient encapsulation of miR-34a and Let7a mimics by aqueous self-assembly for dual EGFR/CD44- targeted delivery; (2) evaluate transfection, phenotypic, and epigenetic reprogramming with miR-34a and Let7a mimics in wild-type and drug resistant A549 NSCLC and SKOV3 OC cells and 3D spheroids models; (3) examine in vivo tumor targeting, biodistribution, and quantitative pharmacokinetic profiles with control and dual EGFR/CD44-targeted HA-based nanoparticles in orthotopic wild-type and resistant A549 NSCLC and SKOV3 OC tumor models; (4) evaluate in vivo transfection and cellular reprogramming with systemically-administered miR-34a and miR-Let7a mimics in orthotopic wild-type and resistant NSCLC and OC tumor models; and (5) examine the therapeutic efficacy and acute safety profiles of miR transfection with chemotherapy in orthotopic wild-type and resistant NSCLC and OC tumor models. This study is clinically significant as a strategy for enhancing the therapeutic efficacy of MDR cancer treatment through cellular reprogramming by using a miR-based therapeutic approach to phenotypically and epigenetically reprogram NSCLC and OC. Our HA-based nanoparticle platform is highly innovative and versatile for dual EGFR/CD44 targeted and intracellular delivery of nucleic acid constructs in orthotopic refractory NSCLC and OC tumors.

项目摘要 肿瘤的可塑性和多药耐药（MDR）的发展仍然是最重要的 非小细胞肺癌（NSCLC）和卵巢癌的临床治疗面临挑战 （OC）。我们假设非小细胞肺癌中肿瘤细胞的表型和表观遗传重编程， OC可显著改善治疗反应，尤其是难治性疾病。 NCI癌症纳米技术创新研究（IRCN）的主要目标（PAR-14-285） 应用是开发和评估创新的基于microRNA（miR）的表型和表观遗传细胞 使用高度通用的双靶向透明质酸（HA）基纳米平台的重编程方法， 根除获得性MDR。这一目标与IRCN关于可能的研究方向的指导方针是一致的， 开发“克服治疗失败的技术和工具”。 我们的初步结果表明，双重EGFR/CD 44靶向HA纳米颗粒负载miR-34 a， 表达模拟物在转基因表达、改变核和线粒体表观遗传 A549野生型和A549 DDP顺铂耐药NSCLC模型的体外和体内标记。 具体应用目标如下：（1）HA基功能块的“Click”合成 和通过水性自组装有效包封miR-34 a和Let 7a模拟物，用于双重EGFR/CD 44- 靶向递送;（2）评估miR-34 a和Let 7a的转染、表型和表观遗传重编程 野生型和耐药A549 NSCLC和SKOV 3 OC细胞和3D球状体模型中的模拟物;（3） 检查体内肿瘤靶向、生物分布和定量药代动力学特征， EGFR/CD 44靶向HA纳米颗粒在原位野生型和耐药A549 NSCLC和SKOV 3中的应用 OC肿瘤模型;（4）评估全身施用的C57 BL/6的体内转染和细胞重编程; 原位野生型和抗性NSCLC和OC肿瘤模型中的miR-34 a和miR-Let 7a模拟物;和（5） 检查miR转染与化疗的治疗效果和急性安全性特征， 野生型和耐药NSCLC和OC肿瘤模型。 本研究作为提高MDR癌症治疗效果的策略具有临床意义 通过使用基于miR的治疗方法通过细胞重编程进行治疗， 表观遗传学重编程NSCLC和OC。我们基于HA的纳米颗粒平台具有高度创新性， 多功能的EGFR/CD 44双重靶向和细胞内递送核酸构建体， 难治性NSCLC和OC肿瘤。