Sonoporation enhances liposome accumulation and penetration in tumors with low EPR.
Sonoporation enhances liposome accumulation and penetration in tumors with low EPR.
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DOI：
10.1016/j.jconrel.2016.02.021
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发表时间：
2016-06-10
期刊：
影响因子：
--
通讯作者：
Lammers T
中科院分区：
文献类型：
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作者：
Theek B;Baues M;Ojha T;Möckel D;Veettil SK;Steitz J;van Bloois L;Storm G;Kiessling F;Lammers T
增强渗透性和保留（EPR）效应是一种高度可变的现象。为了增强 EPR 介导的被动药物靶向肿瘤，多年来已经评估了几种不同的药理学和物理策略，包括例如TNFα 治疗、血管正常化、热疗和放疗。在这里，我们系统地研究了声孔作用，即超声波（US）和微泡（MB）的结合，对肿瘤积累和脂质体渗透的影响。采用两种不同的MB制剂，并在两种不同的肿瘤模型中评估了它们增强脂质体积累和渗透的能力，这两种肿瘤模型的特征都是相对较低水平的EPR（即高细胞A431表皮样异种移植物和高基质BxPC-3胰腺癌异种移植物）。脂质体标记有两种不同的荧光团，可实现体内计算机断层扫描/荧光分子断层扫描（CT-FMT）和离体双光子激光扫描显微镜（TPLSM）。在这两个模型中，尽管个体间和个体内差异相对较高，但观察到脂质体积累和渗透改善的趋势。在治疗的肿瘤中，脂质体浓度高达未治疗肿瘤的两倍，并且声孔作用增强了脂质体从血管外渗到肿瘤间质的能力。这些发现表明声孔可能是改善 EPR 介导的药物靶向低 EPR 肿瘤的有用策略。
The Enhanced Permeability and Retention (EPR) effect is a highly variable phenomenon. To enhance EPR-mediated passive drug targeting to tumors, several different pharmacological and physical strategies have been evaluated over the years, including e.g. TNFα-treatment, vascular normalization, hyperthermia and radiotherapy. Here, we systematically investigated the impact of sonoporation, i.e. the combination of ultrasound (US) and microbubbles (MB), on the tumor accumulation and penetration of liposomes. Two different MB formulations were employed, and their ability to enhance liposome accumulation and penetration was evaluated in two different tumor models, which are both characterized by relatively low levels of EPR (i.e. highly cellular A431 epidermoid xenografts and highly stromal BxPC-3 pancreatic carcinoma xenografts). The liposomes were labeled with two different fluorophores, enabling in vivo computed tomography / fluorescence molecular tomography (CT-FMT) and ex vivo two-photon laser scanning microscopy (TPLSM). In both models, in spite of relatively high inter- and intra-individual variability, a trend towards improved liposome accumulation and penetration was observed. In treated tumors, liposome concentrations were up to twice as high as in untreated tumors, and sonoporation enhanced the ability of liposomes to extravasate out of the blood vessels into the tumor interstitium. These findings indicate that sonoporation may be a useful strategy for improving EPR-mediated drug targeting to tumors with low EPR.