Selective targeting of liposomes to macrophages using a ligand with high affinity for the macrophage scavenger...

Macrophages play an important role in inflammatory processes and are crucially involved in the onset and progression of atherosclerosis and tumorigenesis. Therefore, macrophages are regarded as an excellent target for therapeutic intervention. Since the scavenger receptor class A (SRA) is highly expressed on macrophages, we developed in the present study an SRA-specific particulate drug carrier by providing phosphatidylcholine liposomes with a targeting ligand for SRA. To enable firm association with liposomes, the high-affinity SRA ligand decadeoxyguanine was covalently attached via a linker to lithocholic oleate (LCO-dA(2)dG(10)). Incorporation of LCO-dA(10)dG(2) into liposomes resulted in an increased electronegative surface charge and a dramatically enhanced serum clearance (t(1/2) < 2 min versus > 5 h). The LCO-dA(2)dG(10)-induced liposome clearance was fully dependent on SRA, as the clearance could be efficiently inhibited by the SRA competitor polyinosinic acid. LCO-dA(2)dG(10) enhanced the affinity of liposomes for SRA in vivo selectively, since introduction of overall or clustered negative charges by other modifications (e.g. oxidation, inclusion of phosphatidylserine, or exposure of glutamic acid residues) did not affect their serum clearance substantially, albeit that these modifications resulted in an at least equally high negative surface charge. LCO-dA(2)dG(10) also increased the association of liposomes with RAW264.7 cells, resulting in an enhanced intracellular delivery and bioactivity of encapsulated dexamethasone-phosphate. Therefore, the SRA-specificity of LCO-dA(2)dG(10)-liposomes may be applied for the specific delivery of drugs to macrophages, which may be of therapeutic benefit in general inflammatory disorders, atherosclerosis, and tumorigenesis.