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

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. 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. A 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. This 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. In 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. In 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

Eu-doped barium aluminium oxynitride with the ß-alumina-type structure as new blue-emitting phosphor

Attractive new blue-emitting phosphors for use in low-pressure mercury gas discharge lamps are synthesized by Eu-substitution in the barium aluminum oxynitride host lattice with the -alumina-type structure. The emission spectra of these phosphors for 254 nm excitation show a band at about 450 nm with a shoulder at higher wavelength. The maximum quantum efficiency of these materials is about 85–90% just like commercial BaMgAl10O17:Eu with the -alumina type structure. The nonoptimized oxynitride phosphors are more sensitive to oxidation (at 873 K) and to short-term depreciation due to 185 nm irradiation compared to commercial BaMgAl10O17:Eu. However, the maintenance of the oxynitride phosphors in single component fluorescent lamps is improved. Calculations indicate that by using these phosphors in tricolor fluorescent lamps instead of BaMgAl10O17:Eu with the -alumina type structure, the color rendering index will improve while the lumen output remains high

Recent advances in liposomal-based anti-inflammatory therapy

Liposomes can be seen as ideal carriers for anti-inflammatory drugs as their ability to (passively) target sites of inflammation and release their content to inflammatory target cells enables them to increase local efficacy with only limited systemic exposure and adverse effects. Nonetheless, few liposomal formulations seem to reach the clinic. The current review provides an overview of the more recent innovations in liposomal treatment of rheumatoid arthritis, psoriasis, vascular inflammation, and transplantation. Cutting edge developments include the liposomal delivery of gene and RNA therapeutics and the use of hybrid systems where several liposomal bilayer features, or several drugs, are combined in a single formulation. The majority of the articles reviewed here focus on preclinical animal studies where proof-of-principle of an improved efficacy-safety ratio is observed when using liposomal formulations. A few clinical studies are included as well, which brings us to a discussion about the challenges of clinical translation of liposomal nanomedicines in the field of inflammatory diseases.Nephrolog

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels 50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715.Prostatic carcinom

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

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. 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. A 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. This 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. In 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. In 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

COMPOSITION FOR TREATMENT OF INFLAMMATORY DISORDERS

A pharmaceutical composition for parenteral administration, comprising liposomes composed of non-charged vesicle-forming lipids, including up to 20 mole percent of an amphipathic vesicle-forming lipid derivatised with polyethyleneglycol, and optionally including not more than 10 mole percent of negatively charged vesicle-forming lipids, the liposomes having a selected mean particle diameter in the size range between about 40-200 nm and containing a water soluble corticosteroid for the site-specific treatment of inflammatory disorders, is provided

Composition for treatment of inflammatory disorders

A pharmaceutical composition for parenteral administration, comprising liposomes composed of non-charged vesicle-forming lipids, including up to 20 mole percent of an amphipathic vesicle-forming lipid derivatized with polyethyleneglycol, and optionally including not more than 10 mole percent of negatively charged vesicle-forming lipids, the liposomes having a selected mean particle diameter in the size range between about 40-200 nm and containing a water soluble corticosteroid for the site-specific treatment of inflammatory disorders, is provided