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Annals of the Rheumatic Diseases logoLink to Annals of the Rheumatic Diseases
. 2005 Feb 4;64(8):1132–1136. doi: 10.1136/ard.2004.030759

Treatment of experimental arthritis with poly(D, L-lactic/glycolic acid) nanoparticles encapsulating betamethasone sodium phosphate

M Higaki 1, T Ishihara 1, N Izumo 1, M Takatsu 1, Y Mizushima 1
PMCID: PMC1755606  PMID: 15695536

Abstract

Objective: To examine the therapeutic activity of hydrophilic glucocorticoid encapsulated in PLGA nanoparticles, which have shown slow release and are targeted to inflamed joints after intravenous administration, in experimental arthritis models.

Methods: Betamethasone sodium phosphate (BSP) encapsulated in PLGA nanoparticles with a size of 100–200 nm (PLGA-nanosteroid) was prepared using a modified oil in water emulsion solvent diffusion method with Zn ions and coated with lecithin. Rats with adjuvant arthritis (AA rats) and mice with anti-type II collagen antibody induced arthritis (AbIA mice) were treated intravenously with PLGA-nanosteroid after the initial sign of arthritis.

Results: In AA rats, a 30% decrease in paw inflammation was obtained in 1 day and maintained for 1 week with a single injection of 100 µg of PLGA-nanosteroid. Soft x ray examination 7 days after this treatment showed decreased soft tissue swelling. Moreover, the PLGA-nanosteroid was also highly effective in AbIA mice. A single injection of 30 µg of the PLGA-nanosteroid resulted in almost complete remission of the inflammatory response after 1 week. In contrast, the same dose of free BSP after three administrations only moderately reduced the severity of inflammation. In addition, a histological examination 7 days after the treatment showed a significant decrease of the inflammatory cells in the joints.

Conclusion: The observed strong therapeutic benefit obtained with PLGA-nanosteroid may be due to the targeting of the inflamed joint and its prolonged release in situ. Targeted drug delivery using a sustained release PLGA-nanosteroid is a successful intervention in experimental arthritis.

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Figure 1.

Figure 1

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 Paw inflammation rate of AA rats. Arthritis was induced in Lewis rats as described in the "Materials and methods" section. Inflammation rate (%) = (measured leg volume–leg volume without adjuvant)/(leg volume on day 14–leg volume without adjuvant)x100. The average inflammation rate of seven rats from days 14 to 21 in each group is shown. SEM is within 10%. *p<0.05 (PLGA-nanosteroid v 300 µg BSP); †p<0.01 (PLGA-nanosteroid v vehicle-PLGA nanoparticles).

Figure 2.

Figure 2

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 Results of soft tissue x ray examination of the hind paw of AA rats. The swelling in the paw was assessed by soft tissue x ray examination on day 21 as described in "Materials and methods". (A) Normal rat control; (B) PLGA-nanosteroid (100 µg, intravenously (IV)) treated AA rat; (C) BSP (100 µg) treated AA rat; (D) vehicle-PLGA nanoparticle treated AA rat.

Figure 3.

Figure 3

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 Paw inflammation score of AbIA mice. Arthritis was induced in Balb/c mice as described in the "Materials and methods" section. The average clinical score is shown. SEM is within 10%. *p<0.05 (PLGA-nanosteroid v BSP) ; †p<0.01 (PLGA-nanosteroid v vehicle-PLGA nanoparticles).

Figure 4.

Figure 4

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 Representative histopathology of the front paw of AbIA mice. (A) Normal mouse control; (B) vehicle-PLGA nanoparticle treated AbIA mouse; (C) PLGA-nanosteroid (30 µg x1x, IV) treated AbIA mouse. An arrow indicates cellular infiltrations. A yellow bar indicates 5 mm.

Figure 5.

Figure 5

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 Histology score of AbIA mice. The extent of cellular infiltration in AbIA mice treated with PLGA-nanosteroid (30 µg x1, IV), BSP (30 µg, x3, IV), or vehicle-PLGA nanoparticles was determined and graded from 0 to 3 in each paw. Data represent mean (SEM) (seven mice in each group). *p<0.05 (PLGA-nanosteroid v BSP); †p<0.01 (PLGA-nanosteroid v vehicle-PLGA nanoparticles).

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