title: Liposomal nanocarriers for plasminogen activators.
abstract: Several plasminogen activators (PAs) have been found effective in treating different thromboembolic diseases. However, administration of conventional thrombolytic therapy is limited by a low efficacy of present formulations of PAs. Conventional treatments using these therapeutic proteins are associated with several limitations including rapid inactivation and clearance, short half-life, bleeding complications or non-specific tissue targeting. Liposome-based formulations of PAs such as streptokinase, tissue-plasminogen activator and urokinase have been developed to improve the therapeutic efficacy of these proteins. Resulting liposomal formulations were found to preserve the original activity of PAs, promote their selective delivery and improve thrombus targeting. Therapeutic potential of these liposome-based PAs has been demonstrated successfully in various pre-clinical models in vivo. Reductions in unwanted side effects (e.g., hemorrhage or immunogenicity) as well as enhancements of efficacy and safety were achieved in comparison to currently existing treatment options based on conventional formulations of PAs. This review summarizes present achievements in: (i) preparation of liposome-based formulations of various PAs, (ii) development of PEGylated and targeted liposomal PAs, (iii) physico-chemical characterization of these developed systems, and (iv) testing of their thrombolytic efficacy. We also look to the future and the imminent arrival of theranostic liposomal formulations to move this field forward.
authors.affiliation: Department of Pharmacology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic. Electronic address: koudelka@vri.cz.
authors.forename: Stepan
authors.initials: S
authors.lastname: Koudelka
authors.affiliation: International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic; Neurology Department of Masaryk University and St. Anne's University Hospital Brno, Czech Republic.
authors.forename: Robert
authors.initials: R
authors.lastname: Mikulik
authors.affiliation: Department of Pharmacology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic.
authors.forename: Josef
authors.initials: J
authors.lastname: Mašek
authors.affiliation: Department of Pharmacology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic; Department of Immunology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Raška
authors.affiliation: Department of Pharmacology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic.
authors.forename: Pavlína
authors.initials: P
authors.lastname: Turánek Knotigová
authors.affiliation: Institute of Pharmaceutical Science, King's College London, United Kingdom and Global Acorn Ltd, London, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miller
authors.affiliation: Department of Pharmacology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic. Electronic address: turanek@vri.cz.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Turánek
mesh_terms: D000818:Animals; D005341:Fibrinolysin / Q000008:administration & dosage* / Q000627:therapeutic use; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000648:ultrastructure; D008666:Metalloendopeptidases / Q000008:administration & dosage* / Q000627:therapeutic use; D049329:Nanostructures / Q000737:chemistry / Q000648:ultrastructure; D013300:Streptokinase / Q000008:administration & dosage* / Q000627:therapeutic use; D013923:Thromboembolism / Q000188:drug therapy; D015912:Thrombolytic Therapy / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D008081:Liposomes; D013300:Streptokinase; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D008666:Metalloendopeptidases; C022653:auR protein, Staphylococcus aureus
keywords: Fibrin; Liposomes; Platelets; Protein delivery; RGD peptide; Streptokinase; Stroke; Thrombus; Tissue plasminogen activator; Urokinase