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

描述（由申请人提供）：利用小干扰RNA（siRNA）与传统小分子药物组合的癌症疗法具有增强治疗谱以对抗多种类型癌症的巨大潜力，并且在转移性癌症的治疗中特别重要。为了使临床医生能够选择最佳的药物-siRNA组合，理想的递送载体将是多功能的，足以递送siRNA和具有广泛理化性质的药物。重要的是，介孔二氧化硅纳米颗粒（MSN）可以在其内部多孔结构中封装广泛的药物，因此非常适合作为基本的递送平台，在其上可以构建药物-siRNA组合系统。该提案的目的是设计能够将已建立的化疗剂和治疗性siRNA靶向、同时、组合递送到转移性癌症中的MSN。中心假设是，使用含有氧化还原响应性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组合递送到CD 44过表达的乳腺癌肺转移（BrCa）中，与单独使用任一种药物相比，将改善抗癌活性。该项目的总体原理是，联合药物-siRNA递送将通过同时沉默参与癌症进展的基因来敏化癌细胞，同时递送有效的治疗剂。本申请的总体目标将得以实现 通过追求三个具体目标：1）设计、合成和表征用于同时递送药物和siRNA到CD 44过表达癌细胞中的氧化还原响应性多层MSN（RRM-MSN）; 2）体外确定使用RRM-MSN的组合药物-siRNA递送是否改善BrCa细胞中的抗癌活性;和3）在体内确定使用RRM-MSN的同时药物-siRNA递送是否改善了在CD 44-过表达BrCa的肺转移模型中的抗肿瘤活性。该方法是创新的，因为具有氧化还原触发的药物和siRNA释放的纳米颗粒的多功能和模块化多层设计，其适合于递送广泛的药物-siRNA组合。这项研究意义重大，因为它将建立一种广泛适用的通用方法，用于同时靶向递送化疗药物和治疗性siRNA，以改善转移性癌症的递送和治疗效果。

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.