Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, MD 21231, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, MD 21205, USA.
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
J Control Release. 2018 Jan 28;270:246-259. doi: 10.1016/j.jconrel.2017.12.005. Epub 2017 Dec 9.
Tumor-targeted drug delivery systems are promising for their advantages in enhanced tumor accumulation and reduced toxicity towards normal organs. However, few nanomedicines have been successfully translated into clinical application. One reason is the gap between current pre-clinical and clinical studies. The prevalent in vitro models utilized in pre-clinical phase are mainly based on the two-dimensional (2D) cell culture and are limited by the difficulty of simulating three-dimensional physiological conditions in human body, such as three-dimensional (3D) architecture, cell heterogeneity, nutrient gradients and the interaction between cells and the extracellular matrix (ECM). In addition, traditional animal models have drawbacks such as high-cost, long periods and physiological differences between animal and human. On the other hand, the employment of 3D tumor cell culture models, especially multicellular tumor spheroids (MCTS), has increased significantly in recent decades. These models have been shown to simulate 3D structures of tumors in vitro with relatively low cost and simple protocols. Currently, MCTS have also been widely exploited in drug delivery system research for comprehensive study of drug efficacy, drug penetration, receptor targeting, and cell recruitment abilities. This review summarizes the delivery barriers for nano-carriers presented in tumor microenvironment, the characteristics and formation methods for applicable multicellular tumor spheroid culture models and recent studies related to their applications in tumor-targeted drug delivery system research.
肿瘤靶向药物递送系统因其在增强肿瘤积累和降低对正常器官的毒性方面的优势而备受关注。然而，很少有纳米药物成功转化为临床应用。其中一个原因是当前临床前和临床研究之间存在差距。临床前阶段中常用的流行体外模型主要基于二维（2D）细胞培养，受到模拟人体三维生理条件的困难的限制，例如三维（3D）结构、细胞异质性、营养梯度以及细胞与细胞外基质（ECM）之间的相互作用。此外，传统动物模型存在成本高、周期长以及动物与人类之间存在生理差异等缺点。另一方面，近年来 3D 肿瘤细胞培养模型的应用，特别是多细胞肿瘤球体（MCTS），显著增加。这些模型已被证明能够以相对较低的成本和简单的方案在体外模拟肿瘤的 3D 结构。目前，MCTS 也已广泛应用于药物递送系统研究，用于全面研究药物疗效、药物渗透、受体靶向和细胞募集能力。本文综述了肿瘤微环境中纳米载体的递药障碍、适用于多细胞肿瘤球体培养模型的特点和形成方法，以及它们在肿瘤靶向药物递送系统研究中的最新应用相关研究。
