Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States.
Nanotechnology Innovation Center of Kansas State (NICKS), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, United States.
ACS Nano. 2020 Mar 24;14(3):3075-3095. doi: 10.1021/acsnano.9b08142. Epub 2020 Mar 4.
Numerous studies have engineered nanoparticles with different physicochemical properties to enhance the delivery efficiency to solid tumors, yet the mean and median delivery efficiencies are only 1.48% and 0.70% of the injected dose (%ID), respectively, according to a study using a nonphysiologically based modeling approach based on published data from 2005 to 2015. In this study, we used physiologically based pharmacokinetic (PBPK) models to analyze 376 data sets covering a wide range of nanomedicines published from 2005 to 2018 and found mean and median delivery efficiencies at the last sampling time point of 2.23% and 0.76%ID, respectively. Also, the mean and median delivery efficiencies were 2.24% and 0.76%ID at 24 h and were decreased to 1.23% and 0.35%ID at 168 h, respectively, after intravenous administration. While these delivery efficiencies appear to be higher than previous findings, they are still quite low and represent a critical barrier in the clinical translation of nanomedicines. We explored the potential causes of this poor delivery efficiency using the more mechanistic PBPK perspective applied to a subset of gold nanoparticles and found that low delivery efficiency was associated with low distribution and permeability coefficients at the tumor site ( < 0.01). We also demonstrate how PBPK modeling and simulation can be used as an effective tool to investigate tumor delivery efficiency of nanomedicines.
大量研究已经设计了具有不同物理化学性质的纳米粒子，以提高向实体瘤的递药效率，但根据一项使用基于 2005 年至 2015 年发表数据的非生理基础建模方法的研究，平均和中位数的递药效率仅分别为注射剂量的 1.48%和 0.70%（%ID）。在本研究中，我们使用基于生理的药代动力学（PBPK）模型分析了涵盖 2005 年至 2018 年发表的广泛纳米药物的 376 组数据集，发现最后采样时间点的平均和中位数递药效率分别为 2.23%和 0.76%ID。此外，静脉给药后 24 h 的平均和中位数递药效率分别为 2.24%和 0.76%ID，168 h 时分别降至 1.23%和 0.35%ID。虽然这些递药效率似乎高于先前的发现，但它们仍然相当低，是纳米药物临床转化的一个关键障碍。我们使用更具机械性的 PBPK 视角探索了这种低递药效率的潜在原因，并将其应用于金纳米粒子的子集，发现低递药效率与肿瘤部位的低分布和通透性系数（<0.01）有关。我们还展示了如何使用 PBPK 建模和模拟作为研究纳米药物肿瘤递药效率的有效工具。
