Control of Liposomal Penetration into Three-Dimensional Multicellular Tumor Spheroids by Modulating Liposomal Membrane Rigidity.
Control of Liposomal Penetration into Three-Dimensional Multicellular Tumor Spheroids by Modulating Liposomal Membrane Rigidity.
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DOI：
10.1021/acs.molpharmaceut.7b00051
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发表时间：
2017-04
影响因子：
4.9
通讯作者：
Yuki Takechi-Haraya;Y. Goda;K. Sakai-Kato
中科院分区：
文献类型：
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作者：
Yuki Takechi-Haraya;Y. Goda;K. Sakai-Kato
载药纳米颗粒有效渗透到实体肿瘤中是癌症治疗中的主要挑战。需要探索影响渗透效率的纳米颗粒的物理化学性质，以实现最大的治疗效果。在这里，我们使用共聚焦激光扫描显微镜来评估荧光标记的脂质体渗透到由HeLa细胞组成的三维球体的效率。制备的脂质体由磷脂酰胆碱和不同含量的胆固醇和/或聚乙二醇改性磷脂组成。我们证明了渗透到球状体中的效率随着弯曲模量的增加而增加（即，膜刚性），如通过原子力显微镜测定的（相关系数，0.84）。为了阐明膜刚度有助于脂质体渗透行为的机制，我们还使用单层细胞分析了细胞摄取。我们发现，渗透效率部分解释了细胞的摄取效率，但其他因素，如脂质体的扩散效率在细胞间隙的肿瘤球体的贡献。我们的研究结果定量地表明，脂质体膜的弯曲模量是脂质体渗透到三维球体的主要决定因素。本研究将有助于理解和控制脂质体制剂的肿瘤渗透。
Effective penetration of drug-carrying nanoparticles into solid tumors is a major challenge in cancer therapy. Exploration of the physicochemical properties of nanoparticles that affect penetration efficiency is required to achieve maximum therapeutic effects. Here, we used confocal laser scanning microscopy to evaluate the efficiencies of penetration of fluorescently labeled liposomes into three-dimensional spheroids composed of HeLa cells. The prepared liposomes were composed of phosphatidylcholines and varying contents of cholesterol and/or a polyethylene glycol-modified phospholipid. We demonstrated that the efficiency of penetration into spheroids increased with the bending modulus (i.e., membrane rigidity) of the liposome, as determined by atomic force microscopy (correlation coefficient, 0.84). To clarify the mechanism by which membrane rigidity contributes to the penetration behavior of liposomes, we also analyzed the cellular uptake using monolayer cells. We showed that penetration efficiency was explained partially by cellular uptake efficiency, but that other factors such as liposome diffusion efficiency in the intercellular space of tumor spheroids contributed. Our results quantitatively demonstrate that the bending modulus of the liposomal membrane is a major determinant of liposomal penetration into three-dimensional spheroids. The present study will contribute to the understanding and control of tumor penetration of liposomal formulations.