Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking.
Doxorubicin as a molecular nanotheranostic agent: effect of doxorubicin encapsulation in micelles or nanoemulsions on the ultrasound-mediated intracellular delivery and nuclear trafficking.
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DOI：
10.1021/mp100269f
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发表时间：
2010-12-06
影响因子：
4.9
通讯作者：
Rapoport N
中科院分区：
文献类型：
--
作者：
Mohan P;Rapoport N
阿霉素 (DOX) 是最常用的化疗药物之一，由于 DOX 分子固有的荧光，也是一种流行的研究工具。 DOX注射后，器官或细胞的荧光成像可以提供药物生物分布的信息。 DOX 分子结合了治疗和成像功能，使其成为出色的治疗诊断剂。然而，DOX 荧光取决于许多因素，在解释 DOX 荧光测量结果时应考虑这些因素。讨论这些问题是本文的主旨。 DOX 荧光强度对 DOX 浓度、局部微环境以及与模型细胞成分相互作用的敏感性通过配对 DOX/磷脂、DOX/组蛋白、DOX/DNA 以及三重 DOX/组蛋白/DNA 和 DOX/磷脂/DNA 系统的荧光光谱来说明。 DOX 荧光在插入 DNA 后会急剧猝灭； DOX 荧光在高浓度的分子溶解 DOX 下也会自猝灭；相反，DOX 荧光在与组蛋白结合或分配到 PEG-磷脂胶束的磷脂相或聚合物胶束的疏水核心后增加。虽然流式细胞术通常用于表征 DOX 细胞内摄取，但 DOX 荧光的上述方面可能会使流式细胞术结果的解释变得非常复杂。通过流式细胞术测量的高细胞荧光可能会提供有关实际细胞内 DOX 浓度的欺骗性信息，并且如果 DOX 未渗透到细胞核中的作用位点，则可能与治疗效果无关。这些问题在封装在聚环氧乙烷-聚己内酯 (PEG-PCL) 胶束或 PEG-PCL 稳定的全氟化碳纳米液滴中的 DOX 的细胞内运输实验中得到了说明，无论是否使用超声波作为外部触发。为了有效封装在胶束核心中，DOX 通常被去质子化，从而去除正电荷并增强 DOX 分子的疏水性。结果发现，去质子化的DOX在细胞质中积累，但没有渗透到细胞核中。封装在胶束或纳米液滴中的 DOX 也是如此，这可能解释了它们在没有超声波的情况下疗效较低的原因。超声波触发 DOX 运输到细胞核中，这在存在纳米乳液的情况下尤其明显，纳米乳液在超声波作用下转化为微泡。微泡空化导致质膜和核膜瞬时透化，从而使 DOX 渗透到细胞核中，从而显着增强 DOX 负载纳米液滴系统的治疗效果。
Doxorubicin (DOX) is one of the most commonly used chemotherapeutic drugs and a popular research tool due to the inherent fluorescence of the DOX molecule. After DOX injection, fluorescence imaging of organs or cells can provide information on drug biodistribution. Therapeutic and imaging capabilities combined in a DOX molecule make it an excellent theranostic agent. However, DOX fluorescence depends on a number of factors that should be taken into consideration when interpreting results of DOX fluorescence measurements. Discussing these problems is the main thrust of the current paper. The sensitivity of DOX fluorescence intensity to DOX concentration, local microenvironment, and interaction with model cellular components is illustrated by fluorescence spectra of paired DOX/phosphilipid, DOX/histone, DOX/DNA, and triple DOX/histone/DNA and DOX/phospholipid/DNA systems. DOX fluorescence is dramatically quenched upon intercalation into the DNA; DOX fluorescence is also self-quenched at high concentrations of molecularly dissolved DOX; in contrast, DOX fluorescence is increased after binding to the histone or partitioning into the phospholipid phase of PEG-phospholipid micelles or hydrophobic cores of polymeric micelles. While flow cytometry is commonly used for characterization of DOX intracellular uptake, the above aspects of DOX fluorescence may significantly complicate interpretation of flow cytometry results. High cell fluorescence measured by flow cytometry may provide deceptive information on the actual intracellular DOX concentration and may not correlate with the therapeutic efficacy if DOX does not penetrate into the site of action in cell nuclei. These problems are illustrated in the experiments on the intracellular trafficking of DOX encapsulated in poly(ethylene oxide)-co-polycaprolactone (PEG-PCL) micelles or PEG-PCL stabilized perfluorocarbon nanodroplets, with and without the application of ultrasound used as an external trigger. For efficient encapsulation in micelle cores, DOX is usually deprotonated, which removes the positive charge and enhances hydrophobicity of DOX molecule. It was found that the deprotonated DOX accumulated in the cell cytoplasm but did not penetrate into the cell nuclei. The same was true for the DOX encapsulated in micelles or nanodroplets, which may explain their low therapeutic efficacy in the absence of ultrasound. Ultrasound triggers DOX trafficking into the cell nuclei, which is especially pronounced in the presence of nanoemulsions that convert into microbubbles under the ultrasound action. Microbubble cavitation results in the transient permeabilization of both plasma and nuclear membranes thus allowing DOX penetration into the cell nuclei, which dramatically enhances therapeutic efficacy of DOX-loaded nanodroplet systems.
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影响因子：
8.8
作者：
Adamo, V.;Lorusso, V.;Rossello, R.;Adamo, B.;Ferraro, G.;Lorusso, D.;Condemi, G.;Priolo, D.;Di Lullo, L.;Paglia, A.;Pisconti, S.;Scambia, G.;Ferrandina, G.
通讯作者：
Ferrandina, G.
影响因子：
5.8
作者：
Alakhov, V;Klinski, E;Kabanov, A
通讯作者：
Kabanov, A
影响因子：
6.1
作者：
Berthiaume, J. M.;Wallace, K. B.
通讯作者：
Wallace, K. B.
影响因子：
2.8
作者：
Dayton, Paul A.;Zhao, Shukui;Ferrara, Katherine W.
通讯作者：
Ferrara, Katherine W.
DOI：
10.1109/tuffc.2009.1132
发表时间：
2009-05
期刊：
IEEE transactions on ultrasonics, ferroelectrics, and frequency control
影响因子：
--
作者：
Fabiilli ML;Haworth KJ;Fakhri NH;Kripfgans OD;Carson PL;Fowlkes JB
通讯作者：
Fowlkes JB