PEGylated Liposomes Accumulate in the Areas Relevant to Skin Toxicities via Passive Extravasation across "Leaky" Endothelium.
PEGylated Liposomes Accumulate in the Areas Relevant to Skin Toxicities via Passive Extravasation across "Leaky" Endothelium.
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DOI：
10.1021/acsnano.2c00423
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发表时间：
2022-04-26
期刊：
影响因子：
17.1
通讯作者：
Simberg, Dmitri
中科院分区：
文献类型：
--
作者：
Li, Yue;Lofchy, Laren;Wang, Guankui;Gaikwad, Hanmant;Fujita, Mayumi;Simberg, Dmitri
聚乙二醇化脂质体是现代药物传递的基石平台。不幸的是，如聚乙二醇化阿霉素脂质体(又名Doxil®)所示，阿霉素药代动力学改变会导致皮肤(包括手掌和脚)非靶点蓄积，从而导致严重的剂量限制毒性。除了Doxil外，其他纳米粒和聚乙二醇化脂质体在皮肤中也有显著的沉积，但其蓄积机制尚不清楚。利用体外成像和体外共聚焦显微镜，我们发现聚乙二醇化脂质体在小鼠体内主要积聚在机械应力/压力的区域。足部皮肤中的血管似乎特别容易渗漏，表现出爆裂状的渗出。在高分辨共聚焦显微镜下观察到两种渗出模式：1)作为完整的脂质体；2)作为分离的脂质体组分。另一方面，稳定的交联型氧化铁纳米虫只以完整的纳米颗粒的形式渗出。除胞吐作用外，脂质体与胞外体标记CD81之间没有共定位。此外，用标记脂质体对福尔马林固定的足部皮肤进行原位灌流显示，渗出是由被动的、能量无关的扩散所介导的，而不是由白细胞的“搭便车”所介导的。这些发现提高了我们对纳米载体在与皮肤病理相关的区域的外渗途径的理解，并可能导致预防和治疗脂质体诱导的皮肤毒性的策略。
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 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 crosslinked 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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影响因子：
17.1
作者：
Kumar R;Roy I;Ohulchanskky TY;Vathy LA;Bergey EJ;Sajjad M;Prasad PN
通讯作者：
Prasad PN
影响因子：
4.6
作者：
Egawa, Gyohei;Nakamizo, Satoshi;Natsuaki, Yohei;Doi, Hiromi;Miyachi, Yoshiki;Kabashima, Kenji
通讯作者：
Kabashima, Kenji
影响因子：
5.4
作者：
Grange C;Tapparo M;Bruno S;Chatterjee D;Quesenberry PJ;Tetta C;Camussi G
通讯作者：
Camussi G
影响因子：
7.3
作者：
Andreu Z;Yáñez-Mó M
通讯作者：
Yáñez-Mó M
影响因子：
15.9
作者：
Liu, Xiangsheng;Lin, Paulina;Meng, Huan
通讯作者：
Meng, Huan