A d-Peptide Ligand of Integrins for Simultaneously Targeting Angiogenic Blood Vasculature and Glioma Cells,Molecular Pharmaceutics

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A d-Peptide Ligand of Integrins for Simultaneously Targeting Angiogenic Blood Vasculature and Glioma Cells
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2018-01-16 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00944
Yachao Ren _{1,

2,

3} , Changyou Zhan _{1,

2,

4,

5} , Jie Gao _{1,

2} , Mingfei Zhang _{1,

2} , Xiaoli Wei _{1,

2} , Man Ying _{1,

2} , Zining Liu _{1,

2} , Weiyue Lu _{1,

2,

6,

7}

Affiliation

The current prognosis of glioma patients remains poor after intensive multimodal treatments, which is partially due to the existence of the blood–brain tumor barrier (BBTB). In the present study, a novel “bifunctional ligand” (termed ^DVS) was developed by retro-inverso isomerization. ^DVS is a ligand of integrins highly expressed on glioma cells and tumor neovasculature. ^DVS exhibited exceptional stability in serum and demonstrated significantly higher targeting efficiency for glioma and HUVEC cells compared with the parent L-peptide. As a result, ^DVS modified micelles (^DVS-MS) exhibited high encapsulation efficiency of doxorubicin, ideal size distribution, and sustained release behavior of the payload. In vivo studies showed that ^DVS-MS could target and efficiently deliver fluorescence to tumor cells and tumor vasculature not only in the mice bearing subcutaneous tumors but also in those bearing intracranial tumors. Moreover, doxorubicin loaded ^DVS modified micelles exerted potent tumor growth inhibitory activity against subcutaneous and intracranial human glioma in comparison to drug loaded plain micelles and ^LVS modified micelles. Therefore, ^DVS appears to be a suitable targeting ligand with potential applications for glioma targeted drug delivery.

中文翻译：

整合素的d肽配体同时靶向血管生成的血管和神经胶质瘤细胞

接受密集的多式联运治疗后，神经胶质瘤患者的当前预后仍然很差，部分原因是存在血脑肿瘤屏障（BBTB）。在本研究中，通过逆反异构化开发了一种新型的“双功能配体”（称为^D VS）。^D VS是在神经胶质瘤细胞和肿瘤新脉管系统上高表达的整联蛋白的配体。与母体L-肽相比，^D VS在血清中表现出出色的稳定性，并显示出对神经胶质瘤和HUVEC细胞的明显更高的靶向效率。结果，^D VS修饰的胶束（^D VS-MS）表现出高的阿霉素包封效率，理想的粒径分布以及有效载荷的持续释放性能。体内研究表明，^D VS-MS不仅可以靶向并有效地将荧光传递至肿瘤细胞和肿瘤脉管系统，不仅在患有皮下肿瘤的小鼠中，而且在具有颅内肿瘤的小鼠中也是如此。而且，与药物装载的普通胶束和^L VS修饰的胶束相比，载有阿霉素的^D VS修饰的胶束对皮下和颅内人神经胶质瘤具有有效的肿瘤生长抑制活性。因此，^D VS似乎是一种合适的靶向配体，在神经胶质瘤靶向药物递送中具有潜在的应用。

更新日期：2018-01-16

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