Abstract
Despite the nowadays available plentitude of strategies to selectively introduce functional surface modification of liposomes, in preclinical research this process is still primarily performed after liposomal preparation utilizing comprised activated phospholipids with functionalized head groups. However, because these activated lipids are present during the liposomal preparation process, they can cross-react with incorporated drugs, especially the particularly often utilized active esters and maleimide groups. Macromolecular drugs, being composed of amino acids, are particularly prone to such cross-reactions due to their often multiple reactive functionalities such as amino and disulfide groups. To demonstrate this impact on the formulation in liposomal surface modification, we assessed the extent of cross-reaction during the liposomal preparation of two activated phospholipids with typically used head group functionalized phospholipids, with the two peptide drugs vancomycin and insulin comprising disulfide and amino functionalities. Both drugs revealed a considerable fraction of covalent modification (estimated 2 to 12%) generated during the liposome preparation process with comprised activated lipids. Modification of the active pharmaceutical ingredients (APIs) was determined by high-resolution mass spectrometric analysis. These findings clearly demonstrate the non-negligibility of potential cross reactions using the post preparation liposomal surface modification strategy in preclinical research.
Highlights
Surface-modified liposomes, with conventional PEGylated liposomes left aside, have become a popular tool for a variety of applications in drug delivery such as cancer targeting as well as oral and intracellular delivery [1,2,3,4,5]
The incorporation of activated lipid did not noticeably affect liposomal characteristics. Both activated lipids were incorporated in an amount of 1 mol-% without changing the size, polydispersity index (PDI), and lamellarity compared to control liposomes consisting solely of lecithin and cholesterol
No change in characteristics occurred when activated lipids were incorporated in liposomes containing the model compounds vancomycin or insulin (Table 1)
Summary
Surface-modified liposomes, with conventional PEGylated liposomes left aside, have become a popular tool for a variety of applications in drug delivery such as cancer targeting as well as oral and intracellular delivery [1,2,3,4,5]. The plentitude of applications can be traced back to the easy-to-handle process of liposomal modification. Due to the authorities’ requirements on the unity of liposomal formulations, preparation under regulatory compliance must (and will) avoid side reactions or variance on the amount of bilayer. Expeditious manufacturing methods are enjoying continued popularity. Because of this discrepancy, the transfer of preclinical results into regulatory settings may be hampered
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