Journal
JOURNAL OF CONTROLLED RELEASE
Volume 282, Issue -, Pages 25-34Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2018.05.002
Keywords
Nanomedicine; Tumor targeting; Vascular normalization; EPR; HRG; pHPMA; Drug delivery
Funding
- European Research Council [ERC-StG-309495-NeoNaNo]
- European Fund for Regional Development [I3-STM EU-EFRE-0800387]
- German Research Foundation (DFG) [LA 2937/1-2, SFB 1066, SFB/TRR 57, GR 5027/2-1]
- Czech Science Foundation [GA CR 16-17207S]
- Aachen Interdisciplinary Center for Clinical Research (IZKF) [O3-1, O3-2]
- RWTH Aachen University [rwth0178]
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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.
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