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）与传统小分子药物结合的癌症疗法具有巨大的潜力，可以增强治疗手段，对抗多种类型的癌症，在转移性癌症的治疗中尤为重要。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，能够递送具有广泛物理化学性质的siRNA和药物。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，因此非常适合作为构建药物- sirna组合系统的基本递送平台。本提案的目的是设计能够靶向，同时，联合递送已建立的化疗药物和治疗sirna到转移性癌症的MSN。中心假设是，与单独使用任何一种药物相比，使用含有氧化还原反应的sirna结合层和透明质酸（HA）胶体稳定和靶向层的多层MSN将药物- sirna组合递送到cd44过表达的乳腺癌（BrCa）肺转移灶中，将提高抗癌活性。该项目的总体原理是，在提供有效治疗的同时，通过沉默参与癌症进展的基因，联合药物- sirna递送将使癌细胞敏感。此应用程序的总体目标将得到实现

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.