Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner

The blood vessels of cancerous tumours are leaky(1-3) and poorly organized(4-7). This can increase the interstitial fluid pressure inside tumours and reduce blood supply to them, which impairs drug delivery(8,9). Anti-angiogenic therapies-which 'normalize' the abnormal blood vessels in tumours by making them less leaky-have been shown to improve the delivery and effectiveness of chemotherapeutics with low molecular weights(10), but it remains unclear whether normalizing tumour vessels can improve the delivery of nanomedicines. Here, we show that repairing the abnormal vessels in mammary tumours, by blocking vascular endothelial growth factor receptor-2, improves the delivery of smaller nanoparticles (diameter, 12 nm) while hindering the delivery of larger nanoparticles (diameter, 125 nm). Using a mathematical model, we show that reducing the sizes of pores in the walls of vessels through normalization decreases the interstitial fluid pressure in tumours, thus allowing small nanoparticles to enter them more rapidly. However, increased steric and hydrodynamic hindrances, also associated with smaller pores, make it more difficult for large nanoparticles to enter tumours. Our results further suggest that smaller (similar to 12 nm) nanomedicines are ideal for cancer therapy due to their superior tumour penetration.