Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy

PLoS Comput Biol. 2017 Sep 18;13(9):e1005724. doi: 10.1371/journal.pcbi.1005724. eCollection 2017 Sep.

Abstract

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.

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Computer Simulation
  • Dose-Response Relationship, Drug
  • Drug Therapy, Computer-Assisted / methods*
  • Humans
  • Models, Biological*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Neoplasms / physiopathology*
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / physiopathology*
  • Treatment Outcome
  • Tumor Burden / drug effects

Grants and funding

This research is supported in part by TUBITAK Grant Number 113F047 and Republic of Turkey, Ministry of Development Grant Number 2009K120520. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.