Department of Bioengineering, College of Engineering, University of Utah, 30 S 2000 E, Salt Lake City, Utah 84112, United States.
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
J Control Release. 2017 Dec 10;267:31-46. doi: 10.1016/j.jconrel.2017.08.003. Epub 2017 Aug 12.
Navigating intratumoral drug distribution has proven to be one of the most challenging aspects of drug delivery. The barriers are significant and varied; increased diffusional distances, elevated interstitial fluid pressure, regions of dense extracellular matrix and high cell density, and overall heterogeneity. Such a long list imposes significant requirements on nano-sized carriers. Unfortunately, other capabilities are eclipsed by the distribution requirements. A drug can do no good until it reaches its target. Numerous strategies to improve drug distribution have been developed, taking account of various unique characteristics of solid tumors, including some mechanisms that are still not fully understood. Most of these strategies were from small animal tumor models which are our primary tool for understanding cancer physiology. The small animal tumor model is the most versatile and effective means of understanding tumor transport, but its prevalence belies some of its weaknesses. Tumors grown under lab conditions are developed much more quickly than naturally developed cancers, potentially impacting tumor heterogeneity, blood vessel development, extracellular matrix organization, cell diversity, and many other features of structure and physiology that may impact transport. These problems come in addition to the difficulties of making precise measurements within a living tumor. Resolving these problems is best done by improving our analysis methods, and by finding complementary models that can clarify and expound the details. In this review, we will first discuss some of the strategies employed to improve transport and then highlight some of the new models that have recently been developed in the Bae lab and how they may aid in the study of tumor transport in the future.
肿瘤内药物分布一直是药物传递中最具挑战性的方面之一。障碍很多且各不相同；扩散距离增加、细胞间液压力升高、细胞外基质密集区和细胞密度高以及整体异质性等。如此长的清单对纳米载体提出了很高的要求。不幸的是，其他能力被分配要求所掩盖。药物只有到达靶标才能发挥作用。已经开发了许多旨在改善药物分布的策略，这些策略考虑了实体瘤的各种独特特征，包括一些尚未完全理解的机制。这些策略大多来自小动物肿瘤模型，这是我们了解癌症生理学的主要工具。小动物肿瘤模型是了解肿瘤运输的最通用和有效的手段，但它的普及掩盖了其一些弱点。在实验室条件下生长的肿瘤比自然发生的癌症发育得快得多，这可能会影响肿瘤异质性、血管生成、细胞外基质组织、细胞多样性以及可能影响运输的结构和生理学的许多其他特征。除了在活肿瘤内进行精确测量的困难之外，还存在这些问题。通过改进我们的分析方法并找到可以阐明和详述细节的互补模型，就可以最好地解决这些问题。在这篇综述中，我们将首先讨论一些旨在改善运输的策略，然后重点介绍 Bae 实验室最近开发的一些新模型，以及它们如何有助于未来研究肿瘤运输。
