Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, SE-581 83 Linköping, Sweden.
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Bioconjug Chem. 2022 Apr 20;33(4):736-746. doi: 10.1021/acs.bioconjchem.2c00115. Epub 2022 Apr 1.
Liposome-based drug delivery systems are widely used to improve drug pharmacokinetics but can suffer from slow and unspecific release of encapsulated drugs. Membrane-active peptides, based on sequences derived or inspired from antimicrobial peptides (AMPs), could offer means to trigger and control the release. Cholesterol is used in most liposomal drug delivery systems (DDS) to improve the stability of the formulation, but the activity of AMPs on cholesterol-rich membranes tends to be very low, complicating peptide-triggered release strategies. Here, we show a de novo designed AMP-mimetic peptide that efficiently triggers content release from cholesterol-containing lipid vesicles when covalently conjugated to headgroup-functionalized lipids. Binding to vesicles induces peptide folding and triggers a lipid phase separation, which in the presence of cholesterol results in high local peptide concentrations at the lipid bilayer surface and rapid content release. We anticipate that these results will facilitate the development of peptide-based strategies for controlling and triggering drug release from liposomal drug delivery systems.
基于脂质体的药物递送系统被广泛用于改善药物的药代动力学，但可能存在包裹药物缓慢且非特异性释放的问题。基于抗菌肽（AMPs）衍生或受其启发的序列的膜活性肽可以提供触发和控制释放的手段。胆固醇通常用于大多数脂质体药物递送系统（DDS）以提高制剂的稳定性，但 AMP 对富含胆固醇的膜的活性往往非常低，这使得肽触发释放策略变得复杂。在这里，我们展示了一种从头设计的 AMP 模拟肽，当它与头部功能化脂质共价连接时，能够有效地触发含有胆固醇的脂质体囊泡的内容物释放。与囊泡结合诱导肽折叠并触发脂质相分离，在胆固醇存在的情况下，导致脂质双层表面的局部肽浓度升高，并迅速释放内容物。我们预计这些结果将有助于开发基于肽的策略，以控制和触发脂质体药物递送系统中药物的释放。
