Liposomal nano-drugs based on amphipathic weak acid steroid prodrugs for treatment of inflammatory diseases. (20th October 2016)

• Record Type: Journal Article
• Authors: Turjeman, Keren; Barenholz, Yechezkel
• Is Part Of: Journal of drug targeting. Volume 24:Number 9(2016)
• Page Start: 805
• Page End: 820
• Publication Date: 2016-10-20
• Subjects: Glucocorticosteroids -- steroid hemisuccinate derivatives -- drug delivery -- liposomes -- experimental autoimmune encephalomyelitis (EAE) -- rheumatoid arthritis (RA) -- lupus -- malaria; Drug delivery systems -- Periodicals; Drug Delivery Systems; Vehicles; Drug Administration Routes; Drug Evaluation; 615.7
• DOI: 10.1080/1061186X.2016.1236262
• Languages: English
• ISSNs: 1061-186X

Abstract

Abstract: Background: Steroids are the most efficacious anti-inflammatory agents. However, their toxicities and side-effects compromise their clinical application. Various strategies and major efforts were dedicated for formulating viable liposomal glucocorticosteroids (GCs), so far none of these were approved. Objectives: To evaluate these approaches for formulating GC-delivery systems, especially liposomes, and with focus on the Barenholz Lab experience. Methods: We developed PEGylated nano-liposomes (NSSL) remotely loaded with water-soluble amphipathic weak acid GC-prodrugs. Their remote loading results in high, efficient and stable loading to the level that enables human clinical use. We characterized them for their physical chemistry and stability. We demonstrated their therapeutic efficacy in relevant animal models and studied their pharmacokinetics (PK), biodistribution (BD) and pharmacodynamics advantages over the free pro-drugs. Results: Our steroidal nano-drugs demonstrate much superior PK, BD, tolerability and therapeutic efficacies compared to the free pro-drugs and to most drugs currently used to treat these diseases. These nano-drugs act as robust immune-suppressors, affecting cytokines secretion and diminishing hemorrhage and edema. Conclusions: The combination of improved physical-chemistry, PK, BD, tolerability and therapeutic efficacy of these steroidal nano-drugs over the pro-drugs "as-is" support their further clinical development as potential therapeutic agents for treating inflammatory diseases.