Histidine-rich glycoprotein-induced vascular normalization improves EPR-mediated drug targeting to and into tumors

Benjamin Theek, Maike Baues, Felix Gremse, Robert Pola, Michal Pechar, Inka Negwer, Kaloian Koynov, Benjamin Weber, Matthias Barz, Willi Jahnen-Dechent, Gert Storm, Fabian Kiessling, Twan Lammers* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Scopus)
26 Downloads (Pure)

Abstract

Tumors are characterized by leaky blood vessels, and by an abnormal and heterogeneous vascular network. These pathophysiological characteristics contribute to the enhanced permeability and retention (EPR) effect, which is one of the key rationales for developing tumor-targeted drug delivery systems. Vessel abnormality and heterogeneity, however, which typically result from excessive pro-angiogenic signaling, can also hinder efficient drug delivery to and into tumors. Using histidine-rich glycoprotein (HRG) knockout and wild type mice, and HRG-overexpressing and normal t241 fibrosarcoma cells, we evaluated the effect of genetically induced and macrophage-mediated vascular normalization on the tumor accumulation and penetration of 10–20 nm-sized polymeric drug carriers based on poly(N-(2-hydroxypropyl)methacrylamide). Multimodal and multiscale optical imaging was employed to show that normalizing the tumor vasculature improves the accumulation of fluorophore-labeled polymers in tumors, and promotes their penetration out of tumor blood vessels deep into the interstitium.

Original languageEnglish
Pages (from-to)25-34
Number of pages10
JournalJournal of controlled release
Volume282
DOIs
Publication statusPublished - 28 Jul 2018

Keywords

  • UT-Hybrid-D
  • EPR
  • HRG
  • Nanomedicine
  • pHPMA
  • Tumor targeting
  • Vascular normalization
  • Drug delivery

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