Multilayered redox-responsive nanoparticles for delivery of drug-siRNA combinatio

描述(申请人提供)：利用小干扰RNA(SiRNA)与传统小分子药物相结合的癌症治疗方法具有巨大的潜力，可以增强治疗方案以对抗多种类型的癌症，并且在治疗转移性癌症方面尤为重要。为了使临床医生能够选择最佳的药物-siRNA组合，理想的递送载体将具有足够的通用性，以递送siRNA和具有广泛物理化学性质的药物。重要的是，介孔二氧化硅纳米颗粒(MSN)可以将多种药物包裹在其内部的多孔结构中，因此非常适合作为基本的传递平台，在其上可以构建药物-siRNA组合系统。这项建议的目的是设计MSN能够靶向、同时、联合地将已有的化疗药物和治疗性siRNAs输送到转移癌中。中心假设是，使用包含氧化还原响应的siRNA结合层和透明质酸(HA)的胶体稳定和靶向层的多层MSN将药物-siRNA组合输送到CD44高表达的乳腺癌肺转移瘤(BRCA)中，与单独使用这两种药物相比，将提高抗癌活性。该项目的总体理论基础是，联合药物-siRNA传递将通过同时沉默参与癌症进展的基因，同时提供有效的治疗方法来使癌细胞敏感。本应用程序的总体目标将达到 通过追求三个特定的目标：1)设计、合成和鉴定氧化还原响应型多层MSN(RRM-MSN)，用于同时将药物和siRNA输送到CD44高表达的癌细胞；2)体外确定使用RRM-MSN的联合药物-siRNA输送是否提高了BRCA细胞的抗癌活性；以及3)在体内确定使用RRM-MSN同时输送药物-siRNA是否提高了CD44高表达的BRCA肺转移模型的抗肿瘤活性。这种方法是创新的，因为纳米颗粒具有多功能和模块化的多层设计，具有氧化还原触发的药物和siRNA释放，适合于输送广泛的药物-siRNA组合。这项拟议的研究具有重要意义，因为它将建立一种广泛适用和通用的方法，同时靶向输送化疗药物和治疗性siRNA，以改善转移性癌症的输送和治疗结果。

DESCRIPTION (provided by applicant): Cancer therapies that utilize the combination of small interfering RNA (siRNA) with traditional small-molecule drugs have the great potential to enhance the treatment repertoire to combat many types of cancers and are particularly important in the treatment of metastatic cancer. In order to allow clinicians to select optimal drug-siRNA combinations, an ideal delivery vector will be versatile enough to deliver siRNA and drugs ranging broadly in physicochemical properties. Importantly, mesoporous silica nanoparticles (MSN) can encapsulate a broad range of drugs in their internal porous structure and thus are well suited as the basic delivery platform onto which systems of drug-siRNA combinations can be constructed. The objective of this proposal is to design MSN capable of targeted, simultaneous, combined delivery of established chemotherapeutics and therapeutic siRNAs into metastatic cancer. The central hypothesis is that using multilayered MSN containing a redox-responsive, siRNA-binding layer and a colloidally stabilizing and targeting layer of hyaluronic acid (HA) to deliver the drug-siRNA combination into CD44-overexpressing lung metastases of breast cancer (BrCa) will improve anticancer activity as compared to either agent alone. The overall rationale for the project is that the combined drug-siRNA delivery will sensitize the cancer cells by simultaneously silencing genes involved in cancer progression while delivering effective therapeutics. The overall objective of this application will be achieved by pursuing three specific aims: 1) design, synthesize, and characterize redox-responsive multilayered MSN (RRM-MSN) for simultaneous delivery of drugs and siRNA into CD44-overexpressing cancer cells; 2) determine in vitro if combined drug-siRNA delivery using RRM-MSN improves anticancer activity in BrCa cells; and 3) determine in vivo if simultaneous drug-siRNA delivery using RRM-MSN improves antitumor activity in a lung metastasis model of CD44-overexpressing BrCa. The approach is innovative because of the versatile and modular multilayered design of nanoparticles with redox-triggered drug and siRNA release, which is suitable for the delivery of a broad range of drug-siRNA combinations. The proposed research is significant because it will establish a widely applicable and versatile method for simultaneous, targeted delivery of chemotherapeutics and therapeutic siRNAs to improve delivery and therapeutic outcome in metastatic cancer.