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 肿瘤可塑性和多药耐药性（MDR）的发展仍然是最重要的 临床癌症治疗的挑战，尤其是非小细胞肺癌（NSCLC）和卵巢癌的挑战 （OC）。我们假设NSCLC和 OC将显着改善治疗反应，尤其是在难治性疾病中。 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MicroRNA（MIR）基于表型和表观遗传细胞 使用高度用途的双靶向透明质酸（HA）的纳米平台的重新编程方法 根除获得的MDR。该目标与IRCN指南有关的指南一致 开发“克服治疗失败的技术和工具”。 我们的初步结果表明，双EGFR/CD44靶向HA纳米颗粒装有miR-34a 表达模拟物在转化表达，核和线粒体表观遗传方面有效 A549野生型和A549DDP顺铂的NSCLC模型的标记在体外和体内。 应用程序的具体目的如下：（1）基于HA的功能块的“单击”合成 并有效地封装miR-34a和LET7A通过水性自组装模拟双EGFR/CD44-- 目标交付； （2）用miR-34a和LET7A评估转化，表型和表观遗传重编程 模仿野生型和抗药性A549 NSCLC和SKOV3 OC细胞以及3D球体模型的模仿； （3） 检查体内肿瘤靶向，生物分布和对照和双重的定量药代动力学特征 原位野生型和抗性A549 NSCLC和SKOV3中的EGFR/CD44靶向HA的基于HA的纳米颗粒 OC肿瘤模型； （4）评估体内转染和细胞重新编程 MiR-34a和miR-let7a模仿原位野生型和抗性NSCLC和OC肿瘤模型； （5） 检查原位化学疗法的miR转染的治疗效率和急性安全概况 野生型和抗性NSCLC和OC肿瘤模型。 这项研究在临床上是提高MDR癌症治疗效率的策略的临床意义 通过使用基于miR的基于MIR的治疗方法进行表型和 表观遗传重新编程NSCLC和OC。我们基于HA的纳米颗粒平台具有很高的创新性和 多功能针对原位的双重EGFR/CD44针对核酸构建体的细胞内递送 难治性NSCLC和OC肿瘤。