Technical Research and Development, Global Drug Development, Novartis Pharma AG, Basel, Switzerland; Nanomedicines and Theranostics, Institute for Experimental Molecular Imaging, RWTH University HospitalAachen, Aachen, Germany.
Technical Research and Development, Global Drug Development, Novartis Pharma AG, Basel, Switzerland.
Biomaterials. 2018 Sep;178:481-495. doi: 10.1016/j.biomaterials.2018.04.006. Epub 2018 Apr 5.
Glucocorticoids are well established anti-inflammatory agents, however, their use to treat chronic inflammatory diseases is limited due to a number of serious side effects. For example, long-term local treatment of chronic wounds with glucocorticoids is prohibited by dysregulation of keratinocyte and fibroblast function, leading to skin thinning. Here, we developed and tested liposome formulations for local delivery of dexamethasone to primary human macrophages, to drive an anti-inflammatory/pro-resolution phenotype appropriate for tissue repair. The liposomes were loaded with the pro-drug dexamethasone-phosphate and surface-modified with either polyethylene glycol or phosphatidylserine. The latter was used to mimic phosphatidylserine-harboring apoptotic cells, which are substrates for efferocytosis, an essential pro-resolution function. Both formulations induced a dexamethasone-like gene expression signature in macrophages, decreased IL6 and TNFα release, increased secretion of thrombospondin 1 and increased efferocytosis activity. Phosphatidylserine-modified liposomes exhibited a faster uptake, a higher potency and a more robust phenotype induction than polyethylene glycol-modified liposomes. Fibroblast and keratinocyte cell cultures as well as a 3D skin equivalent model showed that liposomes applied locally to wounds are preferentially phagocytosed by macrophages. These findings indicate that liposomes, in particular upon shell modification with phosphatidylserine, promote dexamethasone delivery to macrophages and induce a phenotype suitable to support chronic wound healing.
糖皮质激素是一种成熟的抗炎药物，然而，由于其许多严重的副作用，其在治疗慢性炎症性疾病方面的应用受到限制。例如，长期局部应用糖皮质激素治疗慢性伤口会导致角质形成细胞和成纤维细胞功能失调，从而导致皮肤变薄。在这里，我们开发并测试了用于局部递送达塞米松的脂质体配方，以驱动适合组织修复的抗炎/促解决表型。脂质体负载前药地塞米松磷酸酯，并通过聚乙二醇或磷脂酰丝氨酸进行表面修饰。后者用于模拟含有磷脂酰丝氨酸的凋亡细胞，凋亡细胞是吞噬作用的底物，吞噬作用是一种重要的促解决功能。这两种配方都在巨噬细胞中诱导了类似于地塞米松的基因表达特征，减少了 IL6 和 TNFα 的释放，增加了血栓素 1 的分泌，并增加了吞噬作用活性。与聚乙二醇修饰的脂质体相比，磷脂酰丝氨酸修饰的脂质体具有更快的摄取、更高的效力和更稳健的表型诱导。成纤维细胞和角质形成细胞培养以及 3D 皮肤等效模型表明，局部应用于伤口的脂质体优先被巨噬细胞吞噬。这些发现表明，脂质体，特别是通过磷脂酰丝氨酸进行外壳修饰，可促进地塞米松递送至巨噬细胞，并诱导适合支持慢性伤口愈合的表型。
