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

By Vikash P Chauhan, Triantafyllos Stylianopoulos, John D. Martin, Zoran Popović, Ou Chen, W. Kamoun, Moungi G. Bawendi, Dai Fukumura, Rakesh K. Jain. Nature Nanotechnology, 2012

1,046 citations recorded by the source corpus.

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.

Subfields: Biomaterials, Biomedical Engineering, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0d1831c2f5786af72e65cfee65362aec9f4a2b84

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Citations in the corpus

Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. (2013, background): “doxorubicin (Doxil; Janssen Pharmaceuticals, Beerse, Belgium; Data Supplement Fig S9).(105) Third, vascular normalization can improve the outcome of im-”
The role of mechanical forces in tumor growth and therapy (2014, neutral): “Decrease in vessel wall pore size with vascular normalization restores a transvascular pressure difference [Reproduced from Reference (23)].”
Tumor Targeting via EPR: Strategies to Enhance Patient Responses (2018, methodology): “The use of intermediately dosed antiangiogenic therapy enhanced the accumulation of paclitaxel (albumin-bound; 10 nm) in the tumor mass through restoration of convective drug delivery and through a reduction of the IFP [66], but it did not affect the concentrations of doxorubicin (Doxil®; 100 nm) in”
Size-Dependent Localization and Penetration of Ultrasmall Gold Nanoparticles in Cancer Cells, Multicellular Spheroids, and Tumors in Vivo (2012, neutral): “In addition, the delivery of small nanoparticles (diameter, 12 nm) was improved by vascular normalization in mammary tumors, while hindering the delivery of larger nanoparticles (diameter, 125 nm).(44) When we examined other tissues, we found that 2 and 6nmAuNPs accumulatedmainly in the kidney, with”