Liposomal targeting of glucocorticoids : a novel treatment approach for inflammatory disorders (2003)

Glucocorticoids can be highly effective in a wide range of inflammatory disorders e.g. rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases and psoriasis. However, their application in systemic treatment approaches is limited due to a high incidence of serious adverse effects, especially related to long-term treatment. In addition it is generally assumed that - contrary to the so-called 'disease modifying anti-arthritic drugs' - glucocorticoids only suppress the inflammatory process, leaving the progression of disease-related tissue damage unaffected.\n\n Two aspects can be regarded critical for the efficacy-safety issues related to systemic glucocorticoid treatment. First, the unfavorable pharmacokinetic behavior of glucocorticoids upon intravenous administration, which is characterized by rapid clearance in combination with a large volume of distribution. Therefore high and frequent dosing is often necessary to achieve an effective concentration of glucocorticoid at inflamed target sites. Combined with the second aspect, namely the profound physiological actions of glucocorticoids in many different tissues, this explains the high risk of occurrence of serious adverse effects.\nA drug-targeting approach may be employed to increase the efficacy/safety ratio. One of the most interesting carriers for drug-targeting in inflammatory disorders is the long-circulating liposome system. Long-circulating liposomes are small lipid bilayer vesicles with an aqueous interior that can be used to entrap water-soluble agents. Often water-soluble polymers like poly(ethylene glycol) (PEG) are attached to the surface of these liposomes to reduce adhesion of plasma proteins that would otherwise induce recognition and rapid removal from the circulation by macrophages in liver and spleen. Studies with radiolabels entrapped in long-circulating liposomes have indicated that they can selectively extravasate in sites of pathology (inflammatory tissue and tumors), by virtue of increased permeability of the vascular endothelium at these sites.\n\nThis thesis describes the studies that have been performed to evaluate whether the approach of drug targeting can improve delivery and therefore the efficacy of glucocorticoids in inflammatory disorders. We studied pharmacokinetics, tissue distribution, target localization and therapeutic activity of glucocorticoid-PEG-liposomes in both rat and murine experimental arthritis as well as rat and murine experimental encephalomyelitis. The results of these studies indicate that liposomal encapsulation can dramatically increase the therapeutic efficacy of glucocorticoids in inflammatory disorders. A single injection of 10 mg/kg liposomal prednisolone for instance, resulted in complete reversal of the evoked exacerbation of inflammation for almost a week. In contrast, an equal dose unencapsulated prednisolone was hardly effective. Only a weak effect was observed after repeated daily injections. Our mechanistic studies indeed pointed to increased activity as a result of enhanced accumulation of glucocorticoid at sites of inflammation, realized by virtue of the long-circulating liposomal formulation.\n\nIn addition to the therapeutic use in experimental inflammatory disorders, we explored the therapeutic potential of long-circulating glucocorticoid-liposomes in experimental tumor models. Glucocorticoids have been reported to be active in some experimental cancers, however the effects were controversial and required extreme high and toxic doses. Surprisingly, in different murine experimental tumors we found a profound (> 90%) growth inhibition was found after a single dose of liposomal prednisolone. Histological studies revealed the occurrence of cell death among the majority of the tumor cells and showed a marked effect on the capacity of the tumor to invade healthy tissue. The beneficial effect of our liposomal approach may relate to the ability of long-circulating liposomes to selectively deliver the encapsulated glucocorticoid to tumor-associated inflammatory cells, preventing the tumor to utilize inflammation-driven neovascularization and matrix-degradation for its growth.\nIn conclusion, the studies that are described in this thesis point at a dramatic improvement of the therapeutic value of glucocorticoids when incorporated in long-circulating liposomes as targeting vehicles. These findings may offer perspective in both the field of chronic inflammatory disorders as well as in oncology.