Target-Selective Drug Delivery through Liposomes Labeled with Oligobranched Neurotensin Peptides
Target-Selective Drug Delivery through Liposomes Labeled with Oligobranched Neurotensin Peptides
复制标题
DOI：
10.1002/cmdc.201000463
复制
发表时间：
2011-04-04
期刊：
影响因子：
3.4
通讯作者：
Morelli, Giancarlo
中科院分区：
文献类型：
--
作者：
Falciani, Chiara;Accardo, Antonella;Morelli, Giancarlo
本文报道了细胞毒性药物阿霉素（Doxo）脂质体的结构和体外行为，并在脂质体的外表面修饰了含有4个拷贝的8-13神经降压素（NT）肽的支化部分。新的官能化脂质体DOPC-NT（4）Lys（C-18）（2）通过DOPC磷脂与新的合成两亲性分子NT（4）Lys（C-18）（2）的共聚集获得，NT（4）Lys（C-18）（2）含有用亲脂性部分和四分支亲水性肽NT 8 -13衍生的赖氨酸支架，一种神经降压肽片段，因其在受体结合能力上模拟神经降压肽的能力而众所周知。动态光散射测量表明流体动力学半径（RH）的值为88.3 +/-4.4nm。与纯DOPC脂质体相比，在HT 29人结肠腺癌和TE 671人横纹肌肉瘤细胞（两者均表达神经降压素受体）中测试了含Doxo的DOPC-NT（4）Lys（C-18）（2）脂质体的选择性内化和细胞毒性。在HT 29和TE 671肿瘤细胞中，与纯DOPC脂质体相比，肽官能化的脂质体显示出明显的优势：FACS分析表明，在两种细胞系中，与DOPC纯类似物相比，NT 4-脂质体的荧光信号增加;在HT 29和TE 671细胞系中，DOPC-NT（4）Lys（C-18）（2）-Doxo脂质体的细胞毒性相对于DOPC-Doxo脂质体增加四倍。这些效应可归因于DOPC-NT（4）Lys（C-18）（2）-Doxo脂质体的较高内化速率，这是由于与非选择性地接近质膜的DOPC脂质体相比，NT 4-脂质体结合膜至特定蛋白的较低解离常数驱动的较强结合。
The structure and the in vitro behavior of liposomes filled with the cytotoxic drug doxorubicin (Doxo) and functionalized on the external surface with a branched moiety containing four copies of the 8-13 neurotensin (NT) peptide is reported. The new functionalized liposomes, DOPC-NT(4)Lys(C-18)(2), are obtained by co-aggregation of the DOPC phospholipid with a new synthetic amphiphilic molecule, NT(4)Lys(C-18)(2), which contains a lysine scaffold derivatized with a lipophilic moiety and a tetra-branched hydrophilic peptide, NT8-13, a neurotensin peptide fragment well known for its ability to mimic the neurotensin peptide in receptor binding ability. Dynamic light scattering measurements indicate a value for the hydrodynamic radius (RH) of 88.3 +/- 4.4 nm. The selective internalization and cytotoxicity of DOPC-NT(4)Lys(C-18)(2) liposomes containing Doxo, as compared to pure DOPC liposomes, were tested in HT29 human colon adenocarcinoma and TE671 human rhabdomyosarcoma cells, both of which express neurotensin receptors. Peptide-functionalized liposomes show a clear advantage in comparison to pure DOPC liposomes with regard to drug internalization in both HT29 and TE671 tumor cells: FACS analysis indicates an increase in fluorescence signal of the NT4-liposomes, compared to the DOPC pure analogues, in both cell lines; cytotoxicity of DOPC-NT(4)Lys(C-18)(2)-Doxo liposomes is increased four-fold with respect to DOPC-Doxo liposomes in both HT29 and TE671 cell lines. These effects could to be ascribed to the higher rate of internalization for DOPC-NT(4)Lys(C-18)(2)-Doxo liposomes, due to stronger binding driven by a lower dissociation constant of the NT4-liposomes that bind the membrane onto a specific protein, in contrast to DOPC liposomes, which approach the plasma membrane unselectively.