Applications of functionalized fullerenes in tumor theranostics

Abstract

Functionalized fullerenes with specific physicochemical properties have been developed for cancer diagnosis and therapy. Notably, metallofullerene is a new class of magnetic resonance imaging (MRI) contrast-enhancing agent, and may have promising applications for clinical diagnosis. Polyhydroxylated and carboxyl fullerenes have been applied to photoacoustic imaging. Moreover, in recent years, functionalized fullerenes have shown potential in tumor therapies, such as photodynamic therapy, photothermal treatment, radiotherapy and chemotherapeutics. Their antitumor effects may be associated with the modulation of oxidative stress, anti-angiogenesis, and immunostimulatory activity. While various types of novel nanoparticle agents have been exploited in tumor theranostics, their distribution, metabolism and toxicity in organisms have also been a source of concern among researchers. The present review summarizes the potential of fullerenes as tumor theranostics agents and their possible underlying mechanisms are discussed.

Keywords: Functionalized fullerenes; cancer diagnosis; cancer therapy; nanoparticles; theranostics..

Figure 1

Depiction of (A) Gd@C₆₀[C(COOH)₂]₁₀ , (B) Gd@C₆₀(OH)_x , (C) Gd@C₈₂(OH)₂₂ , (D) C₆₀(OH)_x , (E) C₆₀[C(COOH)₂]₂ . Adapted with permission from .

Figure 2

(A) T1-weighted MRI of (a)Gd@C₈₂(OH)₄₀ and Gd-DTPA phantom at a concentration of 0.05, 0.1, and 0.2 mmol Gd/L, (B) CDF1 mice before and 30 min after i.v. administration of Gd@C₈₂(OH)₄₀ via tail vein as a dose of 5 μmol Gd/kg .

Figure 3

(A) Visible light emission from functionalized fullerenes irradiated with a 785-nm laser . (B) Photoacoustic imaging and 2-D signal mapping of tumors in living mice before (Left) and after (Right) intratumoral injection of polyhydroxy fullerenes .

Figure 4

Treatment of a mice tumor with polyhydroxy fullerenes. (A) Experimental setup for photothermal ablation of tumor with CP-0.25 (chitosan-polyhydroxy fullerenes) nanoparticles. (B) Photographs of mouse tumor 2 hours (Left) and 20 hours (Right) after laser irradiation, only a blister was visible after 20 hours (within dotted lines). (C) Histological sections of remaining tumor stained with hematoxylin and eosin demonstrate areas of necrosis .

Figure 5

Mechanism by which C₆₀(OH)₂₀ suppresses carcinoma metastasis in vivo. (A) (A-C) Photos of lungs after soaking in Bouin's solution showing spontaneous pulmonary breast cancer metastases (white arrows). (B) Administration of C₆₀(OH)₂₀ can decrease oxidative stress, the content of angiogenic factors(TNF-α, VEGF and PDGF) and neovascularization in tumor tissues, inhibition of which diminish transmission of cancer cells to lung tissues .

Figure 6

Possible immune-associated pathways by which Gd@C₈₂(OH)₂₂ nanoparticles inhibit the growth of tumors. (A) In comparison to the untreated saline group, IFN-γ and TNF-α expression levels in mouse tumor tissues increased markedly in the group treated with 0.5 mmol/kg/day Gd@C₈₂(OH)₂₂ nanoparticles. (B)The Gd@C₈₂(OH)₂₂ nanoparticles injected in the abdominal cavity are mostly engulfed by macrophages and other phagocytes through phagocytosis, whilst a few enter the blood directly through the peritoneum or mesentery. The Gd@C₈₂(OH)₂₂ nanoparticles stimulate macrophages and T cells to release several kinds of cytokines, such as, IL-2, IL-4, IL-5, TNF-α and IFN-γ, which then triggers a series of signal pathways of immune responses and possibly promotes tumor cell apoptosis .

Figure 7

(A) Biodistribution of ¹⁶⁶Ho_x@C₈₂(OH)_y in BALB/c mice at 1, 4, 24, and 48 h after injection. The animals were sacrificed, and organs were sampled at 1, 4, 24, and 48 h, followed by measurement of the ¹⁶⁶Ho 80.5 KeV γ-emission . (B) Biodistribution of [Gd@C₈₂(OH)₂₂]_n nanoparticles in tumor-bearing mice (expressed as concentrations of gadolinium element, ng Gd/g wet weight) .