Comparison of anti-angiogenic properties of pristine carbon nanoparticles
© Wierzbicki et al.; licensee Springer. 2013
Received: 14 February 2013
Accepted: 15 April 2013
Published: 26 April 2013
Angiogenesis is vital for tumour formation, development and metastasis. Recent reports show that carbon nanomaterials inhibit various angiogenic signalling pathways and, therefore, can be potentially used in anti-angiogenic therapy. In the present study, we compared the effect of different carbon nanomaterials on blood vessel development. Diamond nanoparticles, graphite nanoparticles, graphene nanosheets, multi-wall nanotubes and C60 fullerenes were evaluated for their angiogenic activities using the in ovo chick embryo chorioallantoic membrane model. Diamond nanoparticles and multi-wall nanotubes showed the greatest anti-angiogenic properties. Interestingly, fullerene exhibited the opposite effect, increasing blood vessel development, while graphite nanoparticles and graphene had no effect. Subsequently, protein levels of pro-angiogenic growth factor receptors were analysed, showing that diamond nanoparticles decreased the expression of vascular endothelial growth factor receptor. These results provide new insights into the biological activity of carbon nanomaterials and emphasise the potential use of multi-wall nanotubes and diamond nanoparticles in anti-angiogenic tumour therapy.
KeywordsCarbon nanoparticles Angiogenesis Graphene Graphite Fullerene Diamond Nanotubes
Angiogenesis is the most common process of new blood vessel development. Growth of new vessels starts from pre-existing ones and consists of two main processes: sprouting (endothelial cell migration) and intussusception (splitting of vessels) [1, 2]. The growth of blood vessels depends on a balance between angiogenesis-promoting and angiogenesis-inhibiting signalling molecules. Vascular network growth is an essential process, especially during embryonic development, tissue remodelling and regeneration. However, disorders in blood vessel development may foster diseases like chronic inflammatory disorders. Development of new vessels is also essential for the growth and metastasis of tumours, in which pro-angiogenic molecules like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) play critical roles. Binding of FGF and especially VEGF, which is considered a major molecule controlling blood vessel morphogenesis, to their tyrosine kinase receptors activates multiple downstream molecules involved in different signalling pathways that lead to increased vascular permeability, cell migration and proliferation . The VEGF receptor KDR (also called Flk-1) and the FGF receptor FGFR are responsible for regulating angiogenesis (for reviews, see [4, 5]).
Therapeutic anti-angiogenic compounds have been extensively studied for anti-tumour therapy. VEGF inhibitors have been approved for clinical use in cancer diseases. However, anti-VEGF therapy is effective only in particular cases and can lead to serious toxicity [6, 7]. Angiogenesis is a complex process regulated by several regulators. Inhibiting only the VEGF signalling pathway seems to be insufficient. Hence, therapeutic agents affecting tumour cells without harming healthy cells are necessary to optimise cancer treatments. Carbon nanomaterials can be used as low-toxicity inhibitors of tumour angiogenesis. It has been demonstrated that nanoparticles of diamond, graphite, graphene, nanotubes and fullerenes display low toxicity [8–11]. Recently, we showed that diamond nanoparticles and microwave-radiofrequency carbon decreased the vascular network in glioblastoma tumours and mRNA levels of VEGFA and bFGF . Furthermore, because of their high surface-to-volume ratio, carbon nanomaterials cause high biological activity and enable easy surface modification [13, 14]. We hypothesised that pristine carbon nanoparticles can affect VEGF and bFGF receptors and inhibit tumour angiogenesis, but the effectiveness of anti-angiogenic activity can vary between different carbon nanostructures. Consequently, the objective of this study was to explore the anti-angiogenic properties of different carbon nanomaterials to find the most efficient for anti-angiogenic tumour therapy.
Comparison of the physical characteristics of the carbon nanoparticles
6 to 8 nm/15 μm
3 to 4 nm
3 to 4 nm
Approximately 50 nm (aggregates)
8 nm/5 to 20 μm
Zeta potential (mV)
Specific surface area
120 to 150 m2/g
540 to 650 m2/g
Approximately 282 m2/g
0.07 to 0.17 m2/ga
CAM implants were made from sterile Waterman filter paper with a diameter of 10 mm. Water (control) or hydrocolloids of nanoparticles of a concentration of 500 mg/L were added to the implants (final amount of nanoparticles on the implant was 0.01 mg). The implants were pre-treated with 3 mg/mL of hydrocortisone sodium succinate (Sigma, St. Louis, MO, USA) and air dried under sterile conditions. Fertilised eggs from Ross line 308 hens were obtained from a certified hatchery and kept for 4 days at 12°C. The eggs were cleaned, sterilised with UVC light and divided into six groups (6 × 20 eggs). Embryos were incubated at standard conditions (temperature 37°C, humidity 60% and turned once per hour). Embryonic day 0 (E0) started when the eggs were placed into the incubator. At day E6, small holes (1 cm2) were made on the shell above air space, the inner membrane was gently stripped off, and the implants were placed on CAM. The chicken embryos were incubated until day 7 of embryonic development, when implants with CAM were prefixed with 1.5 mL of 4% paraformaldehyde. After 30 min of incubation at 4°C, CAM with implants were cut out and fixed at 4°C in 4% paraformaldehyde for 60 min (total fixation time, 90 min). After fixation, the implants were gently stripped off. All measurements were repeated three times minimum.
CAM tissue angiogenesis analysis
CAM tissue morphological analysis
CAM implant morphology and development of capillary vessels were determined with the stereomicroscope described above. CAM cross sections were made with a cryostat (CM 1900, Leica, Wetzlar, Germany). Blocks were cut into 5-μm-thick sections and observed under a light microscope (DM 750, Leica).
Protein levels of CAM KDR and FGFR were examined by Western blot analysis. Protein extracts were prepared with TissueLyser LT (Qiagen, Hilden, Germany) using ice-cold RIPA buffer (150 mM NaCl, 0.5% sodium deoxycholate, 1% NP-40, 0.1% SDS, 50 mM Tris, pH 7.4) with protease and phosphatase inhibitors (Sigma). The protein concentration was determined by the Total Protein Kit, Micro Lowry, Peterson's Modification (Sigma). An equal volume (50 mg) of samples was denatured by the addition of sample buffer (Bio-Rad Laboratories, Munich, Germany) and boiled for 4 min. Proteins were resolved under reductive conditions with SDS-PAGE and transferred onto PVDF membrane (Life Technologies, Gaithersburg, MD, USA). Protein bands were visualised with the GelDoc scanner (Bio-Rad Laboratories), using the fluorescent method of the WesternDot Kit (Life Technologies) and the primary antibodies bGFR (cat. no. F4305-08, USBiological, Swampscott, MA, USA), KDR (cat. no. SAB4300356, Sigma) and GAPDH (cat. no. NB300-327, Novus Biologicals, Cambridge, UK) as loading control (dilutions recommended by the producers). Protein bands were characterised using the Quantity One 1-D analysis software (Bio-Rad Laboratories).
A one-way analysis of variance with the Bonferroni post hoc test was used for multiple comparisons. Differences at P < 0.05 were considered significant. Results are shown as means and standard errors.
Comparison of angiogenesis parameters of vessels with a diameter between 100 and 200 μm
Mean vessel area (mm2)
Mean vessel length (mm)
Number of branch points
Comparison of angiogenesis parameters of vessels with a diameter less than 100 μm
Mean vessel area (mm2)
Mean vessel length (mm)
Number of branch points
Relative percentage of KDR and FGFR protein levels calculated with GAPDH as the loading control
In this work, we compared the anti-angiogenic properties of carbon-based nanomaterials. The measurements were performed using the well-established chicken embryo CAM model [17, 19]. CAM growth is essential for embryo development and is almost complete by 1 to 14 days of embryogenesis . Blood vessel development was examined in the phase of the most intensive vessel growth, which was on day 7 of chicken embryo development .
The present results are consistent with our previous research, demonstrating that ND and microwave-radiofrequency carbon allotrope decreased the vascular network in glioblastoma tumour and, consequently, their volume and weight. Moreover, diamond nanoparticles decreased the mRNA level of the main pro-angiogenic factors VEGFA and bFGF . ND also affected the transcription level of the human stress-responsive genes of cells exposed to stress (heat shock, cytotoxic and oxidative stress). It has been demonstrated that although ND did not show toxic effects on leukaemia cell line HL-60, it up-regulates the expression of the gene SOD1, responsible for the defence mechanism against reactive oxygen species, and down-regulates the genes JUN, GADD45A and FRAP1, responsible for protection against genotoxic and cellular stress . Moreover, the anti-angiogenic activity of nanoparticles has been related to their inhibitory effects on pro-angiogenic factors. Gold nanoparticles specifically bind to VEGFA and bFGF and inhibit their interaction with cell membrane receptors [23, 24].
Among all the tested nanoparticles, only MWNT and more significantly ND showed anti-angiogenic activity. Nanomaterials with graphite structure (NG and GNS) did not alter blood vessel development. There are only a few studies on the biological activity of GNS. Wang et al.  showed that GNS oxide exhibited low toxicity in mice and human fibroblast cells. Furthermore, GNS displayed low cytotoxicity in erythrocytes and fibroblasts , which together with our results suggests that GNS is highly biocompatible with the vascular system. Similarly, NG had no effect on CAM angiogenesis, although they have the same shape and similar size and are produced in the same way (but under different conditions) as ND , which had the strongest anti-angiogenic activity (Table 1). The strongest inhibition of vessel growth by ND may be linked to the inhibition of VEGF receptor (KDR) expression. VEGF is a major pro-angiogenic factor essential for the development of the blood vessel network. It is controlled by the release of growth factors dependent on the oxygen level, with HIF-1 being one of the most important . Hypoxia leads to the up-regulation of VEGF and, thus, the formation of new blood vessels, which consequently normalises the oxygen status. In tumours, high activity and fast divisions of tumour cells lead to oxygen deficiency that enhances vessel growth. KDR is also regulated by various signalling molecules in response to changes in oxygen concentration [28, 29]. Hypoxia leads to KDR up-regulation and activation of the angiogenic signalling cascade [30, 31]. Down-regulation of KDR by ND may decrease hypoxia-mediated angiogenesis and exert efficient and long-lasting anti-angiogenic effects. Moreover, chronic hypoxia can lead to further down-regulation of KDR . MWNT showed anti-angiogenic activity, inhibiting the branching of vessels with a diameter smaller than 100 μm. This indicates that MWNT inhibits the development of smaller/younger vessels only. Our report is consistent with the results of another study showing that pristine MWNT displayed an anti-angiogenic effect on an in vivo VEGFA/bFGF-induced model  and in in vitro HUVEC tubule formation assays . However, doxorubicin conjugated with single-wall nanotubes had the opposite effects .
As expected, nanoparticles had less impact on the development of older vessels. Only ND, which exerted the strongest anti-angiogenic properties, induced a significant decrease in vessel length and the number of branch points. However, ND did not change the area of older vessels (100 to 200 μm). Reduced length and branching without significant changes in vessel area suggest that ND can inhibit the development of vessels with dimensions that slightly exceed 100 μm and smaller. The present results give new insights into the bioactive properties of ND and clearly show that this carbon nanoparticle can be considered for use in low-toxicity anti-angiogenic therapy.
Interestingly, our results demonstrated pro-angiogenic activity of pristine C60, which increased the number of branch points and vessel length. Fullerene C60 has been used to inhibit cancer growth  and is used as photosensitisers in photodynamic therapy . However, Zogovic et al.  studied the effect of nanocrystaline fullerene on melanoma tumour and showed that fullerene, probably by immunosuppression, had tumour-promoting activity and increased the production of nitric oxide (NO), which can promote angiogenesis . Furthermore, other reactive oxygen species can also induce angiogenesis . The ability of C60 to generate reactive oxygen species has been previously demonstrated [41, 42]. NO promotes angiogenesis by up-regulating the expression of the VEGFA receptor , which is consistent with our report. This appears to be the most probable mechanism underlying fullerene pro-angiogenic effects and may only be specific for pristine nanoparticles. Hydroxylated C60 has been shown to protect cells in vitro form oxidative stress, while pristine nanoparticles show pro-oxidant capacity [44, 45]. Moreover, C60 modified with multihydroxylated metal can simultaneously down-regulate more than ten angiogenic factors and significantly decrease the capillary vessels of tumours (average size 1.2 cm in diameter) . Murugesan et al.  demonstrated that pristine MWNT and C60 inhibited the angiogenesis induced by exogenous VEGFA or bFGF. Our results indicated that C60 had the opposite effect on vessels not stimulated by exogenous pro-angiogenic factors. This suggests that C60 can have both anti- and pro-angiogenic activity depending on the physiological state of blood vessels.
We compared the anti-angiogenic properties of pristine carbon nanomaterials. According to our results, the carbon nanomaterials showing the most anti-angiogenic to pro-angiogenic properties were as follows: diamond nanoparticles (anti-angiogenic) - multi-wall nanotubes - graphite nanoparticles (no activity) - graphene nanosheets - fullerene C60 (pro-angiogenic). Only diamond nanoparticles, multi-wall nanotubes and fullerenes showed statistically significant results. Nanoparticles showing anti-angiogenic effects also changed the morphology of CAM by decreasing its thickness. Diamond nanoparticles and fullerene changed the expression level of KDR, but not FGFR, thereby affecting the angiogenic potential of CAM. Multi-wall nanotubes and especially diamond nanoparticle can be considered potential inhibitors of blood vessel growth in anti-angiogenic tumour therapy.
This work was supported by the following grants: NCN 2011/03/N/NZ9/04290 and NCN NN311540840. The report is a part of the doctoral thesis of Mateusz Wierzbicki.
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