Cited by 1,101Nanoparticle-Based Drug DeliveryAngiogenesis and VEGF in CancerBarrier Structure and Function Studies

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

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

DOI 10.1038/nnano.2012.45PMC PMC3370066

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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.

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Authors: Chauhan, V. P., Stylianopoulos, T., Martin, J. D., Popović, Z., Chen, O., Kamoun, W. S., Bawendi, M. G., Fukumura, D., & Jain, R. K.
Affiliations: Harvard University (US)
Massachusetts Institute of Technology (US)
Corresponding author: Jain, Rakesh K.
ORCID: Chauhan, Vikash P.
Stylianopoulos, Triantafyllos
Martin, John D.
Chen, Ou
Bawendi, Moungi G.
Fukumura, Dai
Venue: Nature Nanotechnology
Publisher: Springer Science and Business Media LLC
Published: 2012-04-08
Volume: 7
Issue: 6
Pages: 383-388
ISSN: 1748-3387 (ISSN-L)
1748-3395
DOI: 10.1038/nnano.2012.45
PMC: PMC3370066
OpenAlex: W2126163864
Semantic Scholar: 0d1831c2f5786af72e65cfee65362aec9f4a2b84
Cited by: 1,101
References: 31
Citations by year: 2026: 41 · 2025: 41 · 2024: 69 · 2023: 76 · 2022: 80 · 2021: 103 · 2020: 102 · 2019: 107 · 2018: 89 · 2017: 76 · 2016: 73 · 2015: 71 · 2014: 68 · 2013: 78 · 2012: 26
FWCI: 31.50
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature Nanotechnology (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
Funders: National Cancer Institute (R01CA115767, T32CA073479, R01CA085140, R01CA096915, R24CA085140, P01CA080124, R01CA126642, R01CA098706)
Topics: Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords: anti-angiogenic therapy, nanomedicine delivery, nanoparticle size dependence, interstitial fluid pressure, tumor penetration, tumor vasculature, steric hindrance, mammary tumors
MeSH terms: Animals, Female, Mammary Neoplasms, Experimental, Drug Delivery Systems, Mice, SCID, Angiogenesis Inhibitors, Receptors, Vascular Endothelial Growth Factor, Nanomedicine, Mice, Nanoparticles

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

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