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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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中的挑战，特别是非小细胞肺癌（NSCLC）和卵巢癌 (OC)我们研究了非小细胞肺癌和表观遗传的肿瘤细胞的基因重编程。 OC 将显着提高治疗反应，特别是在难治性疾病中。 NCI 癌症纳米技术创新研究 (IRCN) (PAR-14-285) 的主要目标应用程序是开发和评估基于创新的 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）纳米平台的重编程方法根除获得性 MDR 的目标与 IRCN 可能的研究方向指南一致。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 纳米粒子负载 miR-34a 表达模拟物在转基因表达、核和线粒体表观遗传方面有效 A549 野生型和 A549DDP 顺铂耐药 NSCLC 模型体外和体内标记物。该应用的具体目标如下：（1）“点击”合成基于HA的功能块通过水性自组装对双 EGFR/CD44- miR-34a 和 Let7a 模拟物进行有效封装靶向递送；(2) 评估 miR-34a 和 Let7a 的转染、表型和表观遗传重编程在野生型和耐药 A549 NSCLC 和 SKOV3 OC 细胞和 3D 球体模型中进行模拟 (3) 通过对照和双重检查体内肿瘤靶向、生物分布和定量药代动力学特征原位野生型和耐药 A549 NSCLC 和 SKOV3 中的 EGFR/CD44 靶向 HA 纳米颗粒 OC肿瘤模型；（4）评估全身给药的体内转染和细胞重编程原位野生型和耐药 NSCLC 和 OC 肿瘤模型中的 miR-34a 和 miR-Let7a 模拟物；以及 (5) 检查原位化疗中 miR 转染的治疗效果和急性安全性野生型和耐药性 NSCLC 和 OC 肿瘤模型。这项研究作为增强 MDR 癌症治疗效果的策略具有临床意义使用基于 miR 的治疗方法通过细胞重编程来治疗表型和我们基于 HA 的纳米颗粒平台具有高度创新性和可实现性。多功能，可用于原位核酸构建体的双重靶向和细胞内递送难治性 NSCLC 和 OC 肿瘤。