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

Abstract

The blood vessels of cancerous tumours are leaky1–3 and poorly organized4–7. This can increase the interstitial fluid pressure (IFP) inside tumours and reduce blood supply to them, which impairs drug delivery8–9. 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-weights10, 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 (VEGF) receptor-2, improves the delivery of small nanoparticles (12nm diameter) while hindering the delivery of large nanoparticles (125nm diameter). We utilize a mathematical model to show that reducing vessel wall pore sizes through normalization decreases IFP in tumours, 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 (~12nm) nanomedicines are ideal for cancer therapy, owing to superior tumour penetration.

Field dependent transition to the non-linear regime in magnetic hyperthermia experiments: Comparison between maghemite, copper, zinc, nickel and cobalt ferrite nanoparticles of similar sizes

“…Nevertheless, it is known that larger particle sizes might be influenced by incoherent rotation (curling/vortex-like for soft magnets) or domain-wall motion, which need to be correctly modeled in order to make a fair comparison with experimental data. Not less important, at such large sizes particle agglomeration, lower tumor permeability retention effects 45 and/or colloidal stability issues might not be so easily or safely controlled for real biomedical applications. Those problems might be minimized at the particle size investigated in this work.…”

Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy

“…Rationally scheduled antiangiogenic treatment can transiently normalize tumor vessels, improve vessel perfusion, decrease hypoxia, and enhance cytotoxic therapies (4,(19)(20)(21). In genetic studies, vascular normalization by deletion of Rgs5 increased T-cell infiltration into tumors and substantially improved survival after adoptive T-cell transfer in mice (9).…”

Time-dependent pretreatment with bevacuzimab increases tumor specific uptake of cetuximab in preclinical oral cavity cancer studies

“…33 Empirical studies on tumor vessel pore size and therapeutic uptake suggest that the optimal therapeutic size is somewhere between 12 nm-50 nm for maximal tumor penetrance. 34,35 When considered in the context of our finding that cetuximab was retained in the tumor following bevacuzimab administration, it seems plausible that vessel normalization reduces the tumor vessel pore size to a range that still permits extravasation while limiting intravasation, even with larger monoclonal antibodies.…”