Cellular Transmigration Increases Nanoparticle Penetration Into Solid Tumors.

Delivering nanoparticles to cancer cells requires the penetration of nanoparticles into solid tumors. Nanoparticles predominantly enter solid tumors through blood vessel endothelial cells but then become trapped in the dense extracellular matrix layer. There are two known mechanisms that govern nanoparticle escape from this layer. Smaller nanoparticles slowly diffuse through the matrix into the tumor microenvironment. Larger nanoparticles trapped in the extracellular matrix are internalized and transported deeper into the tumor by macrophages. Here, we determined a third mechanism of nanoparticle penetration through the extracellular matrix. We show that neutrophil transendothelial migration through a remodeled extracellular matrix releases trapped nanoparticles into a less dense matrix microenvironment. We stimulated the transmigration process to increase the delivery of nanoparticles to cancer cells. We found that the three mechanisms are interrelated in allowing nanoparticles to escape the vascular extracellular matrix after entering the tumor. Our approach can lead to the development of strategies to increase the penetration of nanoparticles into the tumor microenvironment for efficient delivery to cancer cells.