Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
Molecules. 2020 Sep 27;25(19):4436. doi: 10.3390/molecules25194436.
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.
尽管目前有许多策略可用于选择性地对脂质体进行功能表面修饰，但在临床前研究中，此过程仍主要在脂质体制备后利用具有官能化头部基团的包含的活化磷脂来进行。然而，由于这些活化脂质存在于脂质体制备过程中，它们可能与所包含的药物发生交叉反应，特别是特别常用的活性酯和马来酰亚胺基团。由于其通常具有多个反应性官能团，如氨基和二硫键，由氨基酸组成的大分子药物特别容易发生这种交叉反应。为了证明这对脂质体表面修饰配方的影响，我们评估了在包含两种常用头部基团官能化磷脂的两种活化磷脂的脂质体制备过程中，两种含有二硫键和氨基官能团的肽药物万古霉素和胰岛素的交叉反应程度。这两种药物在包含的活化脂质的脂质体制备过程中均产生了相当大比例的共价修饰（估计为 2%至 12%）。通过高分辨率质谱分析确定了活性药物成分（API）的修饰。这些发现清楚地表明，在临床前研究中使用后制备脂质体表面修饰策略时，潜在的交叉反应不容忽视。
