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首页> 外文期刊>International Journal of Pharmaceutics >Improvement of pharmacokinetic and antitumor activity of PEGylated liposomal doxorubicin by targeting with N-methylated cyclic RGD peptide in mice bearing C-26 colon carcinomas
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Improvement of pharmacokinetic and antitumor activity of PEGylated liposomal doxorubicin by targeting with N-methylated cyclic RGD peptide in mice bearing C-26 colon carcinomas

机译：通过靶向N-甲基化的环状RGD肽靶向C-26结肠癌小鼠改善PEG化脂质体阿霉素的药代动力学和抗肿瘤活性

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摘要

Cyclic Arg-Gly-Asp (cRGD) pentapeptides engrafted liposomes have attracted considerable attention for targeting integrin receptors on tumor vasculature. In this study PEGylated liposomal doxorubicin (PLD) was decorated with three cRGD peptides including Arg-Gly-Asp-D-Tyr-Cys (RGDyC), Arg-Gly-Asp-D-Phe-Lys (RGDfK) and Arg-Gly-Asp-D-Phe-[N-Methyl]Lys (RGDf[N-Met]K). The in vitro liposome-cell-association and cytotoxicity experiments demonstrated the RGD-PLDs capability of internalization into integrin expressing HUVEC cells via receptor mediated endocytosis. The biodistribution studies revealed that decreasing the hydrophilicity of the peptide greatly reduces the RGD-PLDs blood clearance rate and increases their localization in C-26 colon carcinoma tumor model. Meanwhile, the most selective version, RGDf[N-Met]K, which has intermediate hydrophilicity revealed the lowest unwanted interactions with other integrin presenting sites, further localization in tumor, and lower doxorubicin (Dox) side effects. RGDf[N-Met]K-PLD demonstrated a superior control of tumor growth and increased the survival of mice. In this study, we introduced RGDf[N-Met]K for the first time, as a promising ligand for active targeting of liposomes to solid tumor which merits further investigations.
机译：环状Arg-Gly-Asp（cRGD）五肽嫁接脂质体在靶向肿瘤血管上的整联蛋白受体方面引起了相当大的关注。在这项研究中，用三种cRGD肽修饰PEG化脂质体阿霉素（PLD），包括Arg-Gly-Asp-D-Tyr-Cys（RGDyC），Arg-Gly-Asp-D-Phe-Lys（RGDfK）和Arg-Gly- Asp-D-Phe- [N-甲基] Lys（RGDf [N-Met] K）。体外脂质体-细胞缔合和细胞毒性实验表明，RGD-PLDs通过受体介导的内吞作用内化到表达整合素的HUVEC细胞中。生物分布研究表明，降低肽的亲水性会大大降低RGD-PLD的血液清除率，并增加其在C-26结肠癌肿瘤模型中的定位。同时，具有中等亲水性的最具有选择性的版本RGDf [N-Met] K显示与其他整联蛋白呈递位点的有害相互作用最低，在肿瘤中的进一步定位以及较低的阿霉素（Dox）副作用。 RGDf [N-Met] K-PLD表现出对肿瘤生长的出色控制，并提高了小鼠的存活率。在这项研究中，我们首次引入RGDf [N-Met] K，作为将脂质体主动靶向实体瘤的有前途的配体，值得进一步研究。

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