Potent Angiogenesis Inhibition by the Particulate Form of Fullerene Derivatives

Abstract

Antiangiogenesis is an effective strategy for cancer treatment because uncontrolled tumor growth depends on tumor angiogenesis and sufficient blood supply. Great progress has been made in developing a "molecular" form of angiogenesis inhibitors; however, the narrow inhibition spectrum limits anticancer efficacy as those inhibitors that usually target a few or even a single angiogenic factor among many angiogenic factors might initially be effective but ultimately lead to the failure of the treatment due to the induction of expression of other angiogenic factors. In this work, we report that with a multiple hydroxyl groups functionalized surface, the Gd@C(82)(OH)(22) fullerenic nanoparticles (f-NPs) are capable of simultaneously downregulating more than 10 angiogenic factors in the mRNA level that is further confirmed at the protein level. After studying this antiangiogenesis activity of the f-NPs by cellular experiment, we further investigated its anticancer efficacy in vivo. A two-week treatment with the f-NPs decreased >40% tumor microvessels density and efficiently lowered the speed of blood supply to tumor tissues by approximately 40%. Efficacy of the treatment using f-NPs in nude mice was comparable to the clinic anticancer drug paclitaxel, while no pronounced side effects were found. These findings indicate that the f-NPs with multiple hydroxyl groups serve as a potent antiangiogenesis inhibitor that can simultaneously target multiple angiogenic factors. We propose that using nanoscale "particulate" itself as a new form of medicine (particulate medicine) may be superior to the traditional "molecular" form of medicine (molecular medicine) in cancer treatment.

Molecular mechanism of pancreatic tumor metastasis inhibition by Gd@C 82 (OH) 22 and its implication for de novo design of nanomedicine

“…Contrary to the traditional "molecular" form (one drug molecule only), the clustered binding to MMP-9 imposes the significance of the so-called "particulate" form (multiple molecules [Gd@C 82 (OH) 22 ] n ). A large surface area of the aggregate was proposed to attribute a wide range of inhibition of angiogenic factors [i.e., MMP-2/-9, VEGF, CXC chemokine ligand (Cxcl)1, and FGF6] at the mRNA level (16), as well as a more efficient blockage of tumor blood vessels of chaotic and disordered structures rather than the normal blood vessels under tight regulatory control (6).…”

Keeping it small: towards a molecular definition of nanotoxicology

“…In particular, Gadolinium (Gd) based metallofullerenes are developed as innovative contrast agents, and may also act as anti-cancer agents. Meng et al (56) found that Gd@C 82 (OH) 22 downregulated multiple angiogenic factors and in vivo studies using a MCF-7 human breast cancer xenograft model demonstrated that the metallofullerenol nanoparticles displayed anti-cancer efficacy comparable to the chemotherapeutic drug paclitaxel. In a subsequent study, the same nanoparticles were shown to inhibit cancer metastasis through matrix metalloproteinase (MMP) inhibition (57).…”

Carbon nanoparticles downregulate expression of basic fibroblast growth factor in the heart during embryogenesis

“…This observation is consistent with the results from experiments with mice, which showed that the other form of carbon (endohedral fullerenes with encapsulated gadolinium) downregulates the expression of genes encoding the fibroblast growth factor family (FGF1, FGF3, and FGF6). 39 Furthermore, a decrease in bFGF expression after treatment with carbon nanotubes, fullerenes, or graphite has been reported in previous studies. 11 Observed results are also consistent with our previous study that showed that ND and GR cause a reduction in the concentration of bFGF in glioblastoma cultures in ovo.…”