ACS Nano. 2022 Apr 26;16(4):6349-6358. doi: 10.1021/acsnano.2c00423. Epub 2022 Mar 28.
PEGylated liposome is the cornerstone platform for modern drug delivery. Unfortunately, as exemplified by PEGylated liposomal doxorubicin (aka Doxil), altered doxorubicin pharmacokinetics causes off-target accumulation in the skin, including the palms and feet, leading to severe dose-limiting toxicity. In addition to Doxil, other nanoparticles and PEGylated liposomes exhibit significant deposition in the skin, but mechanisms of accumulation are poorly understood. Using imaging and confocal microscopy, we show that PEGylated liposomes in mice accumulate predominantly in the areas subject to mechanical stress/pressure. Blood vessels in foot skin appear to be especially leaky, exhibiting burst-like extravasations. Using high-resolution confocal microscopy and liposomes labeled with different dyes in the membrane and/or interior, two modes of extravasation were observed: (1) as intact liposomes; (2) as separated liposomal components. On the other hand, stable cross-linked iron oxide nanoworms extravasated only as intact nanoparticles. There was no colocalization between liposomes and exosomal marker CD81, excluding the role of exocytosis. Also, perfusion of formalin-fixed foot skin with labeled liposomes revealed that the extravasation is mediated by passive, energy-independent diffusion and not by leukocyte "hitchhiking". These findings improve our understanding of extravasation pathways of nanocarriers in the areas relevant to skin pathologies and could lead to strategies to prevent and treat liposome-induced skin toxicities.
聚乙二醇化脂质体是现代药物递送的基石平台。不幸的是，正如聚乙二醇化多柔比星脂质体（又名多柔比星脂质体）所例示的，改变的多柔比星药代动力学导致药物在非靶标部位的蓄积，包括手掌和脚掌，导致严重的剂量限制毒性。除了多柔比星脂质体之外，其他纳米颗粒和聚乙二醇化脂质体也在皮肤中表现出明显的蓄积，但蓄积的机制尚不清楚。使用成像和共聚焦显微镜，我们显示聚乙二醇化脂质体在小鼠中主要蓄积在受到机械应力/压力的区域。足部皮肤的血管似乎特别容易渗漏，表现出突发样的外渗。使用高分辨率共聚焦显微镜和用不同染料标记的脂质体，观察到两种外渗模式：（1）作为完整的脂质体；（2）作为分离的脂质体成分。另一方面，稳定交联的氧化铁纳米线仅作为完整的纳米颗粒外渗。脂质体和外泌体标志物 CD81 之间没有共定位，排除了外排作用。此外，用标记的脂质体对福尔马林固定的足部皮肤进行灌注显示，外渗是由被动的、能量非依赖的扩散介导的，而不是由白细胞“搭便车”介导的。这些发现提高了我们对纳米载体在与皮肤病理学相关的区域外渗途径的理解，并可能导致预防和治疗脂质体诱导的皮肤毒性的策略。
