脂质体
外渗
离体
纳米载体
共焦显微镜
体内
药物输送
生物物理学
毒品携带者
药理学
医学
化学
病理
材料科学
纳米技术
细胞生物学
生物
生物技术
作者
Yue Li,Laren A. Lofchy,Guankui Wang,Hanmant Gaikwad,Mayumi Fujita,Dmitri Simberg
出处
期刊:ACS Nano
[American Chemical Society]
日期:2022-03-28
卷期号:16 (4): 6349-6358
被引量:7
标识
DOI:10.1021/acsnano.2c00423
摘要
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 ex vivo imaging and ex vivo 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, in situ 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.
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