Vessel normalization and maturation promotes nanoparticle delivery to solid tumors while minimizing metastases.

Nanoparticle delivery to solid tumors is known to be an inefficient process and various studies have tried to increase efficacy, but mechanistic and comparative studies remain scarce. Here, we use pharmacological agents to study the effect of vessel normalization or vessel disintegration on nanoparticle delivery to solid tumors. Using a multiparametric approach, we find that vessel disintegration fails to improve nanoparticle delivery and instead seems to have a limiting effect. Vessel normalization, however, improves delivery efficacy for nanoparticles ranging from 20 to 60 nm diameter. The normalization of the tumor blood vessels results in reduced hypoxia, reduced necrosis and an increase in Plvap+ CD276+ endothelial cells, which have been linked with nanoparticle delivery. Interestingly, where vessel disintegration stimulated cancer cell intravasation and associated metastases, vessel normalization impeded these processes. Together, these data reveal that, vessel normalization may be a safer and more suited approach for improving nanoparticle delivery to solid tumors, but its efficacy is limited by nanoparticle diameter and tumor parameters. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/538559v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@17e5e08org.highwire.dtl.DTLVardef@14f82dcorg.highwire.dtl.DTLVardef@118708eorg.highwire.dtl.DTLVardef@18593d0_HPS_FORMAT_FIGEXP M_FIG C_FIG