Yonucu Sirin, Yιlmaz Defne, Phipps Colin, Unlu Mehmet Burcin, Kohandel Mohammad
Department of Physics, Bogazici University, Bebek, Istanbul, Turkey.
Center for Life Sciences and Technologies, Bogazici University, Bebek, Istanbul, Turkey.
PLoS Comput Biol. 2017 Sep 18;13(9):e1005724. doi: 10.1371/journal.pcbi.1005724. eCollection 2017 Sep.
Tumor-induced angiogenesis leads to the development of leaky tumor vessels devoid of structural and morphological integrity. Due to angiogenesis, elevated interstitial fluid pressure (IFP) and low blood perfusion emerge as common properties of the tumor microenvironment that act as barriers for drug delivery. In order to overcome these barriers, normalization of vasculature is considered to be a viable option. However, insight is needed into the phenomenon of normalization and in which conditions it can realize its promise. In order to explore the effect of microenvironmental conditions and drug scheduling on normalization benefit, we build a mathematical model that incorporates tumor growth, angiogenesis and IFP. We administer various theoretical combinations of antiangiogenic agents and cytotoxic nanoparticles through heterogeneous vasculature that displays a similar morphology to tumor vasculature. We observe differences in drug extravasation that depend on the scheduling of combined therapy; for concurrent therapy, total drug extravasation is increased but in adjuvant therapy, drugs can penetrate into deeper regions of tumor.
肿瘤诱导的血管生成导致缺乏结构和形态完整性的渗漏肿瘤血管的形成。由于血管生成，升高的间质液压力（IFP）和低血液灌注成为肿瘤微环境的常见特征，它们构成了药物递送的障碍。为了克服这些障碍，血管系统的正常化被认为是一种可行的选择。然而，需要深入了解正常化现象以及在哪些条件下它能够实现其前景。为了探索微环境条件和药物给药方案对正常化益处的影响，我们构建了一个包含肿瘤生长、血管生成和IFP的数学模型。我们通过具有与肿瘤血管相似形态的异质血管系统施用抗血管生成药物和细胞毒性纳米颗粒的各种理论组合。我们观察到药物外渗的差异取决于联合治疗的给药方案；对于同步治疗，总药物外渗增加，但在辅助治疗中，药物可以渗透到肿瘤的更深区域。
