School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, 30332-0400, United States.
Acc Chem Res. 2012 Jul 17;45(7):985-93. doi: 10.1021/ar200216f. Epub 2011 Dec 19.
The application of RNA interference to treat disease is an important yet challenging concept in modern medicine. In particular, small interfering RNA (siRNA) have shown tremendous promise in the treatment of cancer. However, siRNA show poor pharmacological properties, which presents a major hurdle for effective disease treatment especially through intravenous delivery routes. In response to these shortcomings, a variety of nanoparticle carriers have emerged, which are designed to encapsulate, protect, and transport siRNA into diseased cells. To be effective as carrier vehicles, nanoparticles must overcome a series of biological hurdles throughout the course of delivery. As a result, one promising approach to siRNA carriers is dynamic, versatile nanoparticles that can perform several in vivo functions. Over the last several years, our research group has investigated hydrogel nanoparticles (nanogels) as candidate delivery vehicles for therapeutics, including siRNA. Throughout the course of our research, we have developed higher order architectures composed entirely of hydrogel components, where several different hydrogel chemistries may be isolated in unique compartments of a single construct. In this Account, we summarize a subset of our experiences in the design and application of nanogels in the context of drug delivery, summarizing the relevant characteristics for these materials as delivery vehicles for siRNA. Through the layering of multiple, orthogonal chemistries in a nanogel structure, we can impart multiple functions to the materials. We consider nanogels as a platform technology, where each functional element of the particle may be independently tuned to optimize the particle for the desired application. For instance, we can modify the shell compartment of a vehicle for cell-specific targeting or evasion of the innate immune system, whereas other compartments may incorporate fluorescent probes or regulate the encapsulation and release of macromolecular therapeutics. Proof-of-principle experiments have demonstrated the utility of multifunctional nanogels. For example, using a simple core/shell nanogel architecture, we have recently reported the delivery of siRNA to chemosensitize drug resistant ovarian cancer cells. Ongoing efforts have resulted in several advanced hydrogel structures, including biodegradable nanogels and multicompartment spheres. In parallel, our research group has studied other properties of the nanogels, including their behavior in confined environments and their ability to translocate through small pores.
RNA 干扰在疾病治疗中的应用是现代医学中一个重要但具有挑战性的概念。特别是小干扰 RNA（siRNA）在癌症治疗方面显示出巨大的潜力。然而，siRNA 表现出较差的药理学性质，这对有效治疗疾病特别是通过静脉内给药途径构成了重大障碍。针对这些缺点，出现了各种纳米颗粒载体，旨在封装、保护和将 siRNA 递送到病变细胞中。作为有效的载体，纳米颗粒必须在整个递送过程中克服一系列生物学障碍。因此，一种有前途的 siRNA 载体方法是使用具有多种功能的动态多功能纳米颗粒。在过去的几年中，我们的研究小组研究了水凝胶纳米颗粒（纳米凝胶）作为治疗剂，包括 siRNA 的候选递药载体。在我们的研究过程中，我们开发了完全由水凝胶成分组成的更高阶结构，其中几种不同的水凝胶化学物质可以在单个构建体的独特隔室中被隔离。在本报告中，我们总结了我们在水凝胶纳米颗粒设计和应用方面的一些经验，重点介绍了这些材料作为 siRNA 递药载体的相关特征。通过在纳米凝胶结构中分层多种正交化学物质，我们可以赋予材料多种功能。我们将纳米凝胶视为一种平台技术，其中颗粒的每个功能元件都可以独立调整，以针对所需的应用优化颗粒。例如，我们可以修饰载体的壳隔室以实现细胞特异性靶向或逃避固有免疫系统，而其他隔室可以包含荧光探针或调节大分子治疗剂的包封和释放。多功能纳米凝胶的原理验证实验已经证明了其效用。例如，使用简单的核/壳纳米凝胶结构，我们最近报道了 siRNA 的递送，以化学增敏耐药卵巢癌细胞。正在进行的努力导致了几种先进的水凝胶结构的出现，包括可生物降解的纳米凝胶和多隔室球体。与此同时，我们的研究小组研究了纳米凝胶的其他性质，包括它们在受限环境中的行为以及它们穿过小孔的迁移能力。
