Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
School of Life Sciences, Northwestern Polytechnical University, Xi'an, China.
Acta Pharmacol Sin. 2018 May;39(5):825-844. doi: 10.1038/aps.2018.33. Epub 2018 Apr 26.
Nanotechnology has been applied extensively in drug delivery to improve the therapeutic outcomes of various diseases. Tremendous efforts have been focused on the development of novel nanoparticles and delineation of the physicochemical properties of nanoparticles in relation to their biological fate and functions. However, in the design and evaluation of these nanotechnology-based drug delivery systems, the pharmacology of delivered drugs and the (patho-)physiology of the host have received less attention. In this review, we discuss important pharmacological mechanisms, physiological characteristics, and pathological factors that have been integrated into the design of nanotechnology-enabled drug delivery systems and therapies. Firsthand examples are presented to illustrate the principles and advantages of such integrative design strategies for cancer treatment by exploiting 1) intracellular synergistic interactions of drug-drug and drug-nanomaterial combinations to overcome multidrug-resistant cancer, 2) the blood flow direction of the circulatory system to maximize drug delivery to the tumor neovasculature and cells overexpressing integrin receptors for lung metastases, 3) endogenous lipoproteins to decorate nanocarriers and transport them across the blood-brain barrier for brain metastases, and 4) distinct pathological factors in the tumor microenvironment to develop pH- and oxidative stress-responsive hybrid manganese dioxide nanoparticles for enhanced radiotherapy. Regarding the application in diabetes management, a nanotechnology-enabled closed-loop insulin delivery system was devised to provide dynamic insulin release at a physiologically relevant time scale and glucose levels. These examples, together with other research results, suggest that utilization of the interplay of pharmacology, (patho-)physiology and nanotechnology is a facile approach to develop innovative drug delivery systems and therapies with high efficiency and translational potential.
纳米技术已广泛应用于药物传递领域，以改善各种疾病的治疗效果。人们投入了巨大的努力来开发新型纳米颗粒，并研究纳米颗粒的物理化学性质与其生物命运和功能之间的关系。然而，在设计和评估这些基于纳米技术的药物传递系统时，所传递药物的药理学和宿主的（病理）生理学受到的关注较少。在这篇综述中，我们讨论了将重要的药理学机制、生理特征和病理因素整合到纳米技术药物传递系统和治疗设计中的情况。本文提供了一些直接的实例，说明了通过利用 1）药物-药物和药物-纳米材料组合的细胞内协同相互作用来克服多药耐药性癌症，2）循环系统的血流方向以最大限度地将药物递送到肿瘤新生血管和过度表达整合素受体的肺转移细胞，3）内源性脂蛋白来修饰纳米载体并将其运送到血脑屏障以治疗脑转移，以及 4）肿瘤微环境中的独特病理因素来开发 pH 和氧化应激响应性混合二氧化锰纳米粒子以增强放射治疗的效果，来进行癌症治疗的这种综合设计策略的原理和优势。关于在糖尿病管理中的应用，设计了一种基于纳米技术的闭环胰岛素输送系统，以在生理相关的时间尺度和葡萄糖水平下提供动态胰岛素释放。这些实例以及其他研究结果表明，利用药理学、（病理）生理学和纳米技术的相互作用是开发高效且具有转化潜力的新型药物传递系统和治疗方法的一种简便方法。
