Liposomes are an excellent drug delivery tool, but they have excellent targeting properties, so to achieve targeting, it is often necessary to add additional targeting materials to the formulation of liposome excipients. This targeting is based on the unique characteristics of target cells, the most common of which are various receptors on the cell surface. Excellent macrophage targeting is critical for Clodronate Liposomes, which relies on improvements in liposome formulations.
Liposome targeting macrophages can be achieved by:
- Alter lipid composition to control physicochemical properties, such as size and charge.
- By adding surface ligands including proteins, peptides, antibodies, polysaccharides, glycolipids, glycoproteins and lectins.
Fig. 1 Summary of liposomal targeting strategies to macrophages (Ciara K, 2011)
Alveolar macrophages and peritoneal macrophages constitutively express high levels of mannose receptor (MR). Hence, mannosylated clodronate liposomes are considered to achieve excellent macrophage targeting.
Mannose and Mannose Receptor
Mannose is one of the carbohydrate components on the surface of many bacterial and viral cells, and the human immune system has evolved multiple mechanisms to recognize pathogens based on mannose recognition.
MR is a C-type lectin 175-kD type I transmembrane protein whose ligands have terminal non-reducing sugars such as mannose, glucose, N-acetylglucosamine and fucose. MRs can recognize and phagocytose pathogens through surface carbohydrate antigens, play numerous roles in immune function, including antigen recognition, endocytosis, and antigen presentation, and are critically involved in homeostasis maintenance, inflammation, and immune responses. Meanwhile, mannose receptor binding is one of the earliest proposed mechanisms for liposome targeting through surface modification of liposomes.
Many studies have confirmed that mannosylated liposomes can preferentially target macrophages. Mannosylation is accomplished by the addition of ligands such as alkyl mannoside, Cholesten-5-yloxy-N-(4-((1-imino-2-thioglycosylethyl)amino)butyl)carboxamide (Mann-C4-Chol). Mann-His-C4-Chol, Man2DOG, 4-aminophenyl-a-D-mannopyranoside and mantriose (Man3)-DPPE added to liposome formulations or by liposome coating of p-aminophenyl-D- Mannopyranoside.
Mannosylated Clodronate Liposomes
Mannosylated clodronate liposomes are a multilamellar liposome suspension in which clodronate is encapsulated in the aqueous compartments of the mannosylated liposomes. The general composition, preparation method and mechanism of action of mannosylated clodronate liposomes are similar to those of standard clodronate liposomes.
Advantages of Mannosylated Clodronate Liposomes
Many mannose-linked liposome derivatives exhibit selective uptake in vitro and distinct biodistribution patterns in vivo, and one study showed that mannosylated (ManDog) clodronate liposomes efficiently deplete in vitro immature cardiomyocytes, while non-mannosylated liposomes have no effect. Huitinga, et al. treated two groups of animals with a liposomal formulation of p-aminophenylmannose-clodronate and a standard formulation in the same experiment. The p-aminophenmannose group did appear to experience fewer clinical symptoms and limited disease progression compared with the standard clodronate liposome group, but no specific reports of macrophage depletion or other between the groups were reported. In conclusion, mannosylated clodronate liposomes may have better efficacy and targeting.
- The product should always be stored in the dark at 4°C, except when brought to room temperature for brief periods before animal dosing. And never freeze them.
- Liposomes may settle for more than a few hours if left undisturbed. Before use, to ensure homogeneity of the liposomal suspension, slowly invert the vial several times until the suspension appears homogeneous by visual inspection.
- Ciara K; et al. Targeted liposomal drug delivery to monocytes and macrophages. Journal of Drug Delivery. 2011, 11; 727241.
- Huitinga I; et al. Suppression of experimental allergic encephalomyelitis in Lewis rats after elimination of macrophages. The Journal of experimental medicine. 1990, 172(4): 1025.
Materials for liposomes
- Cationic Lipid Material
- PEGylated Lipids
- Phosphatidic Acid (PA)
- Phosphatidylcholine (PC)
- Phosphatidylethanolamine (PE)
- Phosphatidylglycerol (PG)
- Phosphatidylserine (PS)