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. 2004 Apr;63(4):348–353. doi: 10.1136/ard.2003.009944

Liposomal targeting of glucocorticoids to synovial lining cells strongly increases therapeutic benefit in collagen type II arthritis

J Metselaar 1, W B van den Berg 1, A Holthuysen 1, M Wauben 1, G Storm 1, P L E M van Lent 1
PMCID: PMC1754935  PMID: 15020326

Abstract

Objective: To investigate the effect of a single intravenous treatment with glucocorticoids (GC) encapsulated in long-circulating PEG-liposomes on both joint inflammation and cartilage destruction and to investigate the phenomenon of selective homing of these liposomes in the inflamed synovium.

Methods: Mice with collagen type II-induced arthritis (CIA) were intravenously treated with liposomal and free prednisolone phosphate (PLP) a few days after the first signs of the disease. Joint inflammation was scored during 1 week after treatment, after which sections of the knee joints were prepared for assessment of cartilage damage. In addition, arthritic mice were treated with liposomes containing colloidal gold. 24 hours after injection, knee joint sections were prepared in which the location of liposomes was visualised.

Results: Treatment of CIA with 10 mg/kg liposomal PLP resulted in a strong and lasting resolution of joint inflammation. 10 mg/kg free PLP only became slightly effective after repeated daily injections. Although joint inflammation recurred 1 week after treatment with liposomal PLP, knee joint sections prepared at this time indicated that the cartilage damage was still reduced. Localisation of gold labelled liposomes in the inflamed joints was seen in the proximity of blood vessels, in the cellular infiltrate, but mainly in the synovial lining. Unaffected joints did not take up liposomes.

Conclusions: By using the property of long-circulating liposomes to target the synovial lining selectively in inflamed joints, the anti-inflammatory activity of GC can be greatly increased, showing also the beneficial effect of reduced cartilage destruction.

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Figure 1 .

Figure 1

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Paw inflammation scores after a single treatment with 10 mg/kg PLP-PEG-liposomes, 1 mg/kg PLP-PEG-liposomes, 10 mg/kg unencapsulated PLP, compared with both empty PEG-liposomes and PBS as controls. In contrast with liposomal PLP, a single treatment with 10 mg/kg unencapsulated PLP had no significant effect (A). Multiple treatment with five daily injections of 10 mg/kg unencapsulated PLP had a significant effect at days 32 and 35 but the effect was no better than that of 1 mg/kg PLP-PEG-liposomes (B). Each point represents the mean of 7 mice (SEM). Arrows indicate treatment.

Figure 2 .

Figure 2

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Effect of liposomal PLP on cartilage loss 1 week after treatment. (A) Knee joint section after treatment with saline; (B) the same knee joint after treatment with 10 mg/kg PLP-PEG-liposomes. Original magnification x200. Haematoxylin and eosin staining. T, tibia; F, femur, JS, joint space; C, cartilage layer.

Figure 3 .

Figure 3

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Histological evaluation of the effect on exudate and infiltrate as measures for inflammation, and on cartilage erosion, of 10 mg/kg liposomal PLP at 1 week after treatment. Data indicate the mean of seven mice (SEM). Asterisks indicate significance (p<0.05).

Figure 4 .

Figure 4

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Visualisation of gold labelled PEG-liposomes. (A) Gold-liposomes in the inflamed knee joint. Original magnification x50. (B) Magnification x100 of an area surrounding the synovial lining. Insert: magnification x200 of an area surrounding blood vessels. Gold particles are visible as black dots. Note that the liposomal gold is mainly localised in the synovial lining and some around blood vessels. Relatively little gold is visible in the cellular infiltrate. (C) Visualisation of gold labelled PEG-liposomes in an unaffected knee joint. Original magnification x50. (D) Spleen localisation of gold labelled PEG liposomes. Original magnification x100. P, patella; F, femur, JS, joint space; CI, cellular infiltrate; SL, synovial lining; V, vessels; WP, white pulp; RP, red pulp.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

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