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.

Biointerface Laboratory RWTH Aachen University Clinic and Helmholtz Institute for Biomedical Engineering Aachen Germany

Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging RWTH Aachen University Clinic and Helmholtz Institute for Biomedical Engineering Aachen Germany

Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging RWTH Aachen University Clinic and Helmholtz Institute for Biomedical Engineering Aachen Germany; Department of Targeted Therapeutics Biomaterial Science and Technology University of Twente Enschede The Netherlands

Department of Nanomedicine and Theranostics Institute for Experimental Molecular Imaging RWTH Aachen University Clinic and Helmholtz Institute for Biomedical Engineering Aachen Germany; Department of Targeted Therapeutics Biomaterial Science and Technology University of Twente Enschede The Netherlands; Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands

Department of Targeted Therapeutics Biomaterial Science and Technology University of Twente Enschede The Netherlands; Department of Pharmaceutics Utrecht Institute for Pharmaceutical Sciences Utrecht University Utrecht The Netherlands

Institute of Macromolecular Chemistry Czech Academy of Science Prague Czech Republic

Institute of Organic Chemistry Johannes Gutenberg University Mainz Germany

Max Planck Institute for Polymer Research Mainz Germany

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