Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner
Open accessAbstract
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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In breast tumor-bearing mice, combination of Doxil (around 125 nm) or Abaxane (around 12 nm) resulted in significant around threefold accumulation of smaller nanoparticles.
“Further, the research group administered a combination of Doxil (around 125 nm in size) or Abaxane (around 12 nm in size) in breast tumor-bearing mice and observed a significant (around threefold) accumulation of smaller nanoparticles [26].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [26]
The Methods (Tumour growth studies) confirm that mice bearing mammary tumours received DC101 with either Doxil or Abraxane. The reported roughly threefold increase, however, was in transvascular flux of separate 12 nm nanoparticle probes after DC101 treatment, not measured accumulation of Abraxane during the combination therapy. The paper gives the drugs’ approximate diameters as 100 nm and 10 nm, respectively. (LLM, conf=0.88)
Experimental — accuracy not yet measuredUniformly elevated IFP in the tumor center is responsible for inhibiting drug delivery.
“The uniformly elevated IFP in tumor center is responsible for inhibiting drug delivery [172, 178, 186] while the steep pressure gradients at the periphery favors tumor growth and metastasis[154,[187][188][189][190].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [186]
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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
- Venue
- Nature Nanotechnology
- Published
- 2012-04-08
- Volume
- 7
- Issue
- 6
- Pages
- 383-388
- ISSN
- 1748-3387 (ISSN-L)
- 1748-3395
- 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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