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Inhibition of inflammatory arthritis using fullerene nanomaterials.

Dellinger AL, Cunin P, Lee D, Kung AL, Brooks DB, Zhou Z, Nigrovic PA, Kepley CL - PLoS ONE (2015)

Bottom Line: It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts.Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls.In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α.

View Article: PubMed Central - PubMed

Affiliation: University of North Carolina Greensboro, Joint School of Nanosceince and Nanoengineering, Greensboro, North Carolina, United States of America.

ABSTRACT
Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.

No MeSH data available.


Related in: MedlinePlus

Fullerenes targets joints in inflammatory arthritis.In Fig 3A, non-arthritic control (left) and arthritic (right) mice were injected intravenously with 50 μg/300μl of IR800 conjugated fullernes and imaged six hours later using the Odyssey imaging system. Control mice (left) without inflammatory arthritis received the same concentration of fullerene-dye. Note the joint localization of the Dye-fullerene conjugate in the arthritic mouse. Fig 3B shows whole mouse imaging and Fig 3C shows imaging of externalized organs performed 24 hours after fullerene-dye injection (50 μg/300 μl). Fluorescence intensity is equally portrayed in all and represent a typical mouse out of three treated in parallel. All of the images have undergone background noise subtraction. Fig 3D shows the quantification of fullerene dye concentration in representative organs from the mouse portrayed in Fig 3B–3C.
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pone.0126290.g003: Fullerenes targets joints in inflammatory arthritis.In Fig 3A, non-arthritic control (left) and arthritic (right) mice were injected intravenously with 50 μg/300μl of IR800 conjugated fullernes and imaged six hours later using the Odyssey imaging system. Control mice (left) without inflammatory arthritis received the same concentration of fullerene-dye. Note the joint localization of the Dye-fullerene conjugate in the arthritic mouse. Fig 3B shows whole mouse imaging and Fig 3C shows imaging of externalized organs performed 24 hours after fullerene-dye injection (50 μg/300 μl). Fluorescence intensity is equally portrayed in all and represent a typical mouse out of three treated in parallel. All of the images have undergone background noise subtraction. Fig 3D shows the quantification of fullerene dye concentration in representative organs from the mouse portrayed in Fig 3B–3C.

Mentions: In order to determine the bio-distribution of fullerene derivatives, in vivo experiments were performed using C70-conjugated to an IR-800 dye. As seen in Fig 3, at seven days after serum (Fig 3A) or vehicle (Fig 3B) injection, during the peak symptom scores, the fullerene dye conjugate is clearly visible six hours post injection in the joints of mice with inflammatory arthritis. In contrast, control mice without inflammatory arthritis receiving the same dose of fullerene-dye conjugates did not demonstrate fullerene-dye accumulation in the joints. These data confirm that specifically derivatived fullerenes are capable of migrating and accumulating within the joints of mice with “active” inflammatory arthritis where they are poised to inhibit the inflammatory cascade. Furthermore, organ evaluation (Fig 3C) revealed ratios reveal that very little fullerene derivative accumulated non-specifically throughout the body, as quantified in Fig 3D.


Inhibition of inflammatory arthritis using fullerene nanomaterials.

Dellinger AL, Cunin P, Lee D, Kung AL, Brooks DB, Zhou Z, Nigrovic PA, Kepley CL - PLoS ONE (2015)

Fullerenes targets joints in inflammatory arthritis.In Fig 3A, non-arthritic control (left) and arthritic (right) mice were injected intravenously with 50 μg/300μl of IR800 conjugated fullernes and imaged six hours later using the Odyssey imaging system. Control mice (left) without inflammatory arthritis received the same concentration of fullerene-dye. Note the joint localization of the Dye-fullerene conjugate in the arthritic mouse. Fig 3B shows whole mouse imaging and Fig 3C shows imaging of externalized organs performed 24 hours after fullerene-dye injection (50 μg/300 μl). Fluorescence intensity is equally portrayed in all and represent a typical mouse out of three treated in parallel. All of the images have undergone background noise subtraction. Fig 3D shows the quantification of fullerene dye concentration in representative organs from the mouse portrayed in Fig 3B–3C.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400016&req=5

pone.0126290.g003: Fullerenes targets joints in inflammatory arthritis.In Fig 3A, non-arthritic control (left) and arthritic (right) mice were injected intravenously with 50 μg/300μl of IR800 conjugated fullernes and imaged six hours later using the Odyssey imaging system. Control mice (left) without inflammatory arthritis received the same concentration of fullerene-dye. Note the joint localization of the Dye-fullerene conjugate in the arthritic mouse. Fig 3B shows whole mouse imaging and Fig 3C shows imaging of externalized organs performed 24 hours after fullerene-dye injection (50 μg/300 μl). Fluorescence intensity is equally portrayed in all and represent a typical mouse out of three treated in parallel. All of the images have undergone background noise subtraction. Fig 3D shows the quantification of fullerene dye concentration in representative organs from the mouse portrayed in Fig 3B–3C.
Mentions: In order to determine the bio-distribution of fullerene derivatives, in vivo experiments were performed using C70-conjugated to an IR-800 dye. As seen in Fig 3, at seven days after serum (Fig 3A) or vehicle (Fig 3B) injection, during the peak symptom scores, the fullerene dye conjugate is clearly visible six hours post injection in the joints of mice with inflammatory arthritis. In contrast, control mice without inflammatory arthritis receiving the same dose of fullerene-dye conjugates did not demonstrate fullerene-dye accumulation in the joints. These data confirm that specifically derivatived fullerenes are capable of migrating and accumulating within the joints of mice with “active” inflammatory arthritis where they are poised to inhibit the inflammatory cascade. Furthermore, organ evaluation (Fig 3C) revealed ratios reveal that very little fullerene derivative accumulated non-specifically throughout the body, as quantified in Fig 3D.

Bottom Line: It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts.Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls.In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α.

View Article: PubMed Central - PubMed

Affiliation: University of North Carolina Greensboro, Joint School of Nanosceince and Nanoengineering, Greensboro, North Carolina, United States of America.

ABSTRACT
Inflammatory arthritis (e.g. rheumatoid arthritis; RA) is a complex disease driven by the interplay of multiple cellular lineages. Fullerene derivatives have previously been shown to have anti-inflammatory capabilities mediated, in part, by their ability to prevent inflammatory mediator release by mast cells (MC). Recognizing that MC can serve as a cellular link between autoantibodies, soluble mediators, and other effector populations in inflammatory arthritis, it was hypothesized that fullerene derivatives might be used to target this inflammatory disease. A panel of fullerene derivatives was tested for their ability to affect the function of human skin-derived MC as well as other lineages implicated in arthritis, synovial fibroblasts and osteoclasts. It is shown that certain fullerene derivatives blocked FcγR- and TNF-α-induced mediator release from MC; TNF-α-induced mediator release from RA synovial fibroblasts; and maturation of human osteoclasts. MC inhibition by fullerene derivatives was mediated through the reduction of mitochondrial membrane potential and FcγR-mediated increases in cellular reactive oxygen species and NF-κB activation. Based on these in vitro data, two fullerene derivatives (ALM and TGA) were selected for in vivo studies using K/BxN serum transfer arthritis in C57BL/6 mice and collagen-induced arthritis (CIA) in DBA/1 mice. Dye-conjugated fullerenes confirmed localization to affected joints in arthritic animals but not in healthy controls. In the K/BxN moldel, fullerenes attenuated arthritis, an effect accompanied by reduced histologic inflammation, cartilage/bone erosion, and serum levels of TNF-α. Fullerenes remained capable of attenuating K/BxN arthritis in mast cell-deficient mice Cre-Master mice, suggesting that lineages beyond the MC represent relevant targets in this system. These studies suggest that fullerene derivatives may hold promise both as an assessment tool and as anti-inflammatory therapy of arthritis.

No MeSH data available.


Related in: MedlinePlus