Treatment of rat arthritides with clodronate-containing liposomes.

Large multilamellar liposomes containing dichloro-methylene-bisphosphonate (clodronate; Clo), a bisphosphonate that becomes toxic when intracellularly concentrated, were used to therapeutically target macrophages (M phi) in rats with established adjuvant arthritis (AA; i.v. on days 10,11,12) or antigen-induced arthritis (AIA; i.v. or i.a. on 3 h, days 1,2). In established AA, i.v. injection of Clo-liposomes led to significant, long-lasting amelioration of clinical parameters, and to reduced destruction of the ankle joint even several weeks after termination of treatment. In the acute phase of established AIA, intravenous treatment induced transient clinical amelioration, but did not counteract joint destruction. I.a. treatment in AIA was ineffective. Systemic treatment with anti-M phi principles induces amelioration of both AA and AIA; the improvement appears more profound in AA, i.e., the model with a more systemic character. Preliminary data indicate that depletion of M phi occurs in the liver rather than in spleen, draining lymph nodes or synovial membrane. In addition, local treatment with the same principle is ineffective in AIA. Therefore, systemic elimination of M phi in different sites may be crucial for effective therapy of arthritis with anti-M phi agents.