Integrated Nano-Therapeutics to Overcome Tumor Plasticity and Resistance

项目总结 肿瘤的可塑性和多药耐药(MDR)的发展仍然是最重要的 临床癌症治疗面临的挑战，特别是非小细胞肺癌和卵巢癌 (OC)。我们假设NSCLC和NSCLC中肿瘤细胞的表型和表观遗传重编程 OC能显著提高疗效，特别是在难治性疾病中。 NCI癌症纳米技术(IRCN)创新研究的主要目标(PAR-14-285) 应用是开发和评估基于创新microRNA(MiR)的表型和表观遗传学细胞 使用基于透明质酸(HA)的高度通用的双靶向纳米平台的重新编程方法 根除获得性MDR。这一目标与IRCN关于可能的研究方向的指南是一致的 开发“克服治疗失败的技术和工具”。 我们的初步结果显示，双重EGFR/CD44靶向负载miR-34a的HA纳米粒 表达模拟物在转基因表达、改变核和线粒体表观遗传学方面有效 A549野生型和A549顺铂耐药非小细胞肺癌模型的体内外标记物。 本申请的具体目的如下：(1)基于HA的功能块的“点击”合成 并通过水相自组装有效地包裹了miR-34a和Let7a，用于双重EGFR/CD44- 靶向传递；(2)评价miR-34a和Let7a的转染性、表型和表观遗传学重编程 在野生型和耐药的A549非小细胞肺癌和SKOV3 OC细胞和三维球体模型中进行模拟； 用对照和DUAL检查体内肿瘤靶向性、生物分布和定量药代动力学 EGFR/CD44靶向HA纳米粒在原位野生型和耐药A549 NSCLC和SKOV3中的作用 OC肿瘤模型；(4)全身给药的体内转染和细胞重编程的评价 MiR-34a和miR-Let7a在原位野生型和耐药NSCLC和OC肿瘤模型中的模拟；以及(5) 原位化疗联合miR基因治疗的疗效及急性安全性研究 野生型耐药NSCLC和OC肿瘤模型。 本研究对于提高MDR肿瘤的治疗效果具有重要的临床意义。 使用基于miR的治疗方法通过细胞重新编程治疗表型和 对NSCLC和OC进行表观遗传学重新编程。我们的基于HA的纳米颗粒平台具有很高的创新性和 多用途的双重EGFR/CD44靶向和细胞内原位核酸递送 难治性非小细胞肺癌和OC肿瘤。

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.