A research team led by Prof. WANG Yucai and Assoc. Prof. JIANG Wei from the University of Science and Technology of China (USTC) of the Chinese Academy of Sciences (CAS) has revealed the mechanism of the tumor vascular basement membranes blocking nanoparticles (NPs) for the first time and developed an immunodriven strategy to increase NP penetration through basement membrane barrier.

The study was published in Nature Nanotechnology on Sept. 14. 

Previous studies on the nanotherapeutic transport from the vasculature to the tumor mainly depended on the Enhanced Permeability and Retention effect (EPR), which believes that NPs can cross the tumor vascular endothelial barrier, the last defense of NP penetration, by exploiting the high permeability of tumor vessels. However, clinical trials discovered that NPs only transport small amount of drugs into the tumor issue, suggesting other mechanisms for hindering NP penetration.

In this study, the research team employed multistep non-invasive intravital microscopy and revealed that the basement membrane that surrounds the endothelial cells and mural cells of tumor vessels severely impedes the extravasation of NPs, forming perivascular NP pools in subendothelial void. 

After accurately analyzing the spatial positioning, microstructure and causes of the NP pools, the team further found enzyme degradation of the basement membrane could significantly reduce the NP pooling, boosting the transport efficiency of nanomedicine.

Based on this finding, they developed an immunodriven strategy by using the localized proteolytic enzymes released by inflammatory leukocytes to create a temporary window on the basement membrane, enabling an explosive release of NPs deep into tumor, and enhancing the enrichment of nanomedicines and therapeutic effect. 

The study provides not only a novel nanomedicine transport strategy distinct from EPR, but also a new theoretical support for the application of nanotherapeutics in cancer, advancing the understanding of transvascular transport mechanism of NPs.