Enhanced Specificity and Drug Delivery in Tumors by cRGD-Anchoring Thermosensitive Liposomes.
Enhanced Specificity and Drug Delivery in Tumors by cRGD-Anchoring Thermosensitive Liposomes.
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DOI：
10.1007/s11095-015-1746-7
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发表时间：
2015-12
影响因子：
3.7
通讯作者：
Koning GA
中科院分区：
文献类型：
--
作者：
Dicheva BM;ten Hagen TL;Seynhaeve AL;Amin M;Eggermont AM;Koning GA
开发具有增加的肿瘤滞留的RGD靶向热敏脂质体，提高肿瘤和血管生成内皮细胞中轻度高温（HT）时的药物释放效率。合成标准热敏脂质体（TSL）和含有具有序列Arg-Cys-D-Phe-Asp-Gly（RGDf[N-Met]C）的环状Arg-Gly-Asp（cRGD）五肽的TSL，负载Dox并表征。温度和时间依赖性的药物释放曲线进行了评估，通过荧光法。流式细胞术和共聚焦显微镜研究细胞内Dox递送。研究了TSL和RGD-TSL对B16 B16黑色素瘤、B16 F10黑色素瘤和HUVEC的细胞毒性作用。对植入背侧皮肤褶皱带窗小鼠中的B16 B16肿瘤进行活体显微镜检查。在常温或初始高热条件下，在B16 B16荷瘤小鼠中跟踪Dox-TSL和Dox-RGD-TSL的药代动力学和生物分布。DLS和cryo-TEM显示颗粒均匀性和约85 nm的尺寸。通过荧光分光光度法评估，阿霉素负载效率> 95%。流式细胞术和共聚焦显微镜显示，与TSL相比，黑色素瘤和内皮细胞特异性摄取RGD-TSL，并增加多柔比星递送。高分辨率活体显微镜检查显示RGD-TSL在肿瘤血管系统中特异性蓄积。此外，热疗的应用导致大量药物从RGD-TSL释放。生物分布研究表明，初始热疗增加了肿瘤从TSL和RGD-TSL的Dox摄取。由于肿瘤和血管生成内皮细胞的更高摄取以及热触发的药物释放，RGD-TSL具有增加药物功效的潜力。本文的在线版本（doi：10.1007/s11095-015-1746-7）包含补充材料，可供授权用户使用。
To develop RGD-targeted thermosensitive liposomes with increased tumor retention, improving drug release efficiency upon mild hyperthermia (HT) in both tumor and angiogenic endothelial cells. Standard termosensitive liposomes (TSL) and TSL containing a cyclic Arg-Gly-Asp (cRGD) pentapeptide with the sequence Arg-Cys-D-Phe-Asp-Gly (RGDf[N-Met]C) were synthetized, loaded with Dox and characterized. Temperature- and time-dependent drug release profiles were assessed by fluorometry. Intracellular Dox delivery was studied by flow cytometry and confocal microscopy. Cytotoxic effect of TSL and RGD-TSL was studied on B16Bl6 melanoma, B16F10 melanoma and HUVEC. Intravital microscopy was performed on B16Bl6 tumors implanted in dorsal-skin fold window-bearing mice. Pharmacokinetic and biodistribution of Dox-TSL and Dox-RGD-TSL were followed in B16Bl6 tumor bearing mice upon normothermia or initial hyperthermia conditions. DLS and cryo-TEM revealed particle homogeneity and size of around 85 nm. Doxorubicin loading efficiency was >95%as assessed by spectrofluorometry. Flow cytometry and confocal microscopy showed a specific uptake of RGD-TSL by melanoma and endothelial cells when compared to TSL and an increased doxorubicin delivery. High resolution intravital microscopy demonstrated specific accumulation of RGD-TSL to the tumor vasculature. Moreover, application of hyperthermia resulted in massive drug release from RGD-TSL. Biodistribution studies showed that initial hyperthermia increases Dox uptake in tumors from TSL and RGD-TSL. RGD-TSL have potency to increase drug efficacy due to higher uptake by tumor and angiogenic endothelial cells in combination with heat-triggered drug release. The online version of this article (doi:10.1007/s11095-015-1746-7) contains supplementary material, which is available to authorized users.