Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region
Development of a novel cyclic RGD peptide for multiple targeting approaches of liposomes to tumor region
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DOI：
10.1016/j.jconrel.2015.10.039
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发表时间：
2015-12-28
影响因子：
10.8
通讯作者：
ten Hagen, Timo L. M.
中科院分区：
文献类型：
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作者：
Amin, Mohamadreza;Mansourian, Mercedeh;ten Hagen, Timo L. M.
含有细胞毒剂和以Arg-Gly-Asp为靶点的脂质体经常被用来对抗肿瘤新生血管中的αvβ3整合素。然而，与许多其他配体修饰的脂质体一样，这些制剂受到网状内皮系统(RES)的增强摄取以及与在正常器官中广泛表达的整合素受体的非靶向相互作用，导致生物分布不良和毒性作用。在这里，我们主要致力于开发一种RGD修饰的脂质体递送系统，以提高靶向选择性和肿瘤摄取。首先，用cRGDfK和RGDyC多肽修饰的空间稳定型阿霉素脂质体(SSLD)具有不同的物理性质。稳定性评估以及体外和体内研究表明，增加多肽的疏水性可以促进RGD-SSLD在C-26肿瘤模型中的治疗效果，这是因为RGD-SSLD对RES和调理的识别减少，并限制了靶外相互作用。然后设计了一种新的N-甲基化RGD多肽，并在体内外对其靶向整合素呈递细胞的能力进行了全面的评估。RGDf[N-甲基]C通过整合素介导的内吞作用促进HUVEC对脂质体的内化。窗口小鼠体内显微镜观察表明，RGDf[N-甲基]C脂质体在小鼠B16F0和人BLM肿瘤模型中具有靶向肿瘤血管和肿瘤细胞的能力。在荷B16F0肿瘤小鼠体内的定量生物分布显示，其对肿瘤的亲和力很高，而对正常器官的亲和力不是很大。大剂量RGDf[N-甲基]C-SSLD的治疗效果优于非靶向SSLD，且无毒副作用。总之，RGDf[N-甲基]C脂质体在靶向肿瘤血管和肿瘤内其他细胞方面很有前途。(C)2015爱思唯尔B.V.保留所有权利。
Liposomes containing cytotoxic agents and targeted with Arg-Gly-Asp based peptides have frequently been used against alpha v beta 3 integrin on tumor neovasculature. However, like many other ligand modified liposomes these preparations suffered from enhanced uptake by the reticulo endothelial system (RES) and off-targeted interaction with integrin receptors vastly expressed in normal organs causing poor biodistribution and toxic effects. Here we mainly focus on development of a RGD-modified liposomal delivery system to enhance both targeting selectivity and tumor uptake. First, sterically stabilized liposomal doxorubicin (SSLD) prepared and decorated with cRGDfK and RGDyC peptides differ in their physical properties. Stability assessments as well as in vitro and in vivo studies revealed that increasing the peptide hydrophobicity promotes the therapeutic efficacy of RGD-SSLD in a C-26 tumor model due to decreased recognition by RES and opsonization and limited off-targeted interactions. Then a novel N-methylated RGD peptide was designed and its capability in targeting integrin presenting cells was comprehensively assessed both in vitro and in vivo. RGDf[N-methyl]C promotes the liposome internalization by HUVEC via integrin mediated endocytosis. Intravital microscopy in window chamber bearing mice illustrated the capability of RGDf[N-methyl]C-liposomes in targeting both tumor vasculature and tumor cells in murine B16F0 and human BLMtumor models. Quantitative biodistribution in mice bearing B16F0 tumor revealed its high affinity to tumor with no considerable affinity to normal organs. Treatment by high dose of RGDf[N-methyl] C-SSLD was found more effective than non-targeted SSLD and no toxic side effect was observed. In conclusion, the RGDf[N-methyl]C-liposome was found promising in targeting tumor vasculature as well as other cells inside the tumor. (C) 2015 Elsevier B.V. All rights reserved.