Dawidczyk Charlene M, Russell Luisa M, Hultz Margot, Searson Peter C
Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD.
Institute for Nanobiotechnology, Johns Hopkins University, Baltimore, MD; Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD.
Nanomedicine. 2017 Jul;13(5):1637-1644. doi: 10.1016/j.nano.2017.02.008. Epub 2017 Feb 28.
Systemic drug delivery to a solid tumor involves a sequence of steps that determine efficacy and survival. Extravasation from circulation at the tumor site is a critical step in this sequence since it regulates how much of the drug accumulates in the tumor. Despite its importance in determining outcomes, extravasation from circulation remains a "black box." The objective of this study is to develop predictive tools for optimization of drug delivery systems. By comparing pharmacokinetics of liposomal doxorubicin in tumor-free and tumor bearing mice we quantitatively assess the rate constants for distribution, elimination, and tumor accumulation. We then relate these rate constants to the tumor-type and drug delivery system. We compare tumor accumulation in three tumor types and show a 10-fold difference between a colorectal adenocarcinoma and a pancreatic adenocarcinoma. Finally, we show how quantitative predictions of changes in tumor accumulation can be used to optimize drug delivery systems.
向实体瘤进行全身药物递送涉及一系列决定疗效和生存期的步骤。药物从肿瘤部位的循环中渗出是这一过程中的关键步骤，因为它决定了有多少药物在肿瘤中蓄积。尽管渗出在决定治疗结果方面很重要，但药物从循环中渗出仍是一个“黑匣子”。本研究的目的是开发用于优化药物递送系统的预测工具。通过比较脂质体阿霉素在无瘤小鼠和荷瘤小鼠体内的药代动力学，我们定量评估了分布、消除和肿瘤蓄积的速率常数。然后，我们将这些速率常数与肿瘤类型和药物递送系统相关联。我们比较了三种肿瘤类型中的肿瘤蓄积情况，结果显示结肠腺癌和胰腺腺癌之间存在10倍的差异。最后，我们展示了如何利用肿瘤蓄积变化的定量预测来优化药物递送系统。
