Antiangiogenic Synergism of Integrin-Targeted Fumagillin Nanoparticles and Atorvastatin in Atherosclerosis
Open accessAbstract
Objectives Studies were performed to develop a prolonged antiangiogenesis therapy regimen based on theranostic alpha(nu)beta(3)-targeted nanoparticles.Background Antiangiogenesis therapy may normalize atherosclerotic plaque vasculature and promote plaque stabilization. alpha(nu)beta(3)-targeted paramagnetic nanoparticles can quantify atherosclerotic angiogenesis and incorporate fumagillin to elicit acute antiangiogenic effects.Methods In the first experiment, hyperlipidemic rabbits received alpha(nu)beta(3)-targeted fumagillin nanoparticles (0, 30, or 90 microg/kg) with either a continued high fat diet or conversion to standard chow. The antiangiogenic response was followed for 4 weeks by cardiac magnetic resonance (CMR) molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles. In a second 8-week study, atherosclerotic rabbits received atorvastatin (0 or 44 mg/kg diet) alone or with alpha(nu)beta(3)-targeted fumagillin nanoparticles (only week 0 vs. weeks 0 and 4), and angiogenesis was monitored with CMR molecular imaging. Histology was performed to determine the location of bound nanoparticles and to correlate the level of CMR enhancement with the density of angiogenic vessels.Results The alpha(nu)beta(3)-targeted fumagillin nanoparticles reduced the neovascular signal by 50% to 75% at 1 week and maintained this effect for 3 weeks regardless of diet and drug dose. In the second study, atherosclerotic rabbits receiving statin alone had no antineovascular benefit over 8 weeks. The alpha(nu)beta(3)-targeted fumagillin nanoparticles decreased aortic angiogenesis for 3 weeks as in study 1, and readministration on week 4 reproduced the 3-week antineovascular response with no carry-over benefit. However, atorvastatin and 2 doses of alpha(nu)beta(3)-targeted fumagillin nanoparticles (0 and 4 weeks) achieved marked and sustainable antiangiogenesis. Microscopic studies corroborated the high correlation between CMR signal and neovessel counts and confirmed that the alpha(nu)beta(3)-targeted nanoparticles were constrained to the vasculature of the aortic adventia.Conclusions The CMR molecular imaging with alpha(nu)beta(3)-targeted paramagnetic nanoparticles demonstrated that the acute antiangiogenic effects of alpha(nu)beta(3)-targeted fumagillin nanoparticles could be prolonged when combined with atorvastatin, representing a potential strategy to evaluate antiangiogenic treatment and plaque stability.
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These nanoparticles decreased the burden of aortic angiogenesis for 3 weeks after treatment.
“In a follow-up study the same group demonstrated that these nanoparticles decreased the burden of aortic angiogenesis for 3 weeks after treatment”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [108]
αVβ3 integrin-specific MRI represents a potential strategy for an anti-angiogenic therapeutic regimen.
“This was determined using αVβ3 integrin-specific MRI, thus representing a potential strategy for an anti-angiogenic therapeutic regimen107,108 (FIG. 3c).”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [108]
The effect of these nanoparticles on aortic angiogenesis was prolonged when combined with oral atorvastatin.
“and that this effect was prolonged when applied in combination with oral atorvastatin (Lipitor; Pfizer) administration.”
From Perspectives and opportunities for nanomedicine in the management of atherosclerosis (2011) · cites this paper as [108]
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- Authors
- Winter, P. M., Caruthers, S. D., Zhang, H., Williams, T. A., Wickline, S. A., & Lanza, G. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Lanza, Gregory M.
- Venue
- JACC: Cardiovascular Imaging
- Publisher
- Elsevier BV
- Published
- 2008-09
- Volume
- 1
- Issue
- 5
- Pages
- 624-634
- ISSN
- 1876-7591 (ISSN-L)
- 1936-878X
- PMC
- PMC2636718
- OpenAlex
- W1969861144
- Cited by
- 166
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 7 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 6 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 8 · 2015: 16 · 2014: 11 · 2013: 10 · 2012: 20
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- JACC. Cardiovascular imaging (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL073646, HL-73646, R01HL078631, HL 78631)
- National Cancer Institute (N01CO27031-16, N01 CO 37007, CA-119342, U54CA136398, U54CA119342)
- National Institute of Allergy and Infectious Diseases (N01 CO037007)
- National Institute of Neurological Disorders and Stroke (R01NS059302)
- National Institute of Biomedical Imaging and Bioengineering (R01EB001704, EB-01704)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
- Keywords
- anti-angiogenic therapy, atorvastatin, integrin αvβ3, atherosclerosis, theranostic nanoparticles, statin combination therapy, aortic adventitia, plaque stabilization, nanoparticle drug delivery, drug synergy
- MeSH terms
- Atorvastatin, Animals, Aorta, Thoracic, Carbocyanines, Cyclohexanes, Disease Models, Animal, Drug Carriers, Drug Synergism, Drug Therapy, Combination, Fatty Acids, Unsaturated, Heptanoic Acids, Heterocyclic Compounds, 1-Ring, Liver, Magnetic Resonance Imaging, Neovascularization, Pathologic, Pyrroles, Rabbits, Sesquiterpenes, Time Factors, Angiogenesis Inhibitors, Integrin alphaVbeta3, Atherosclerosis, Nanoparticles
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