Structure Reconstruction of LyP-1: Lc(LyP-1) Coupling by Amide Bond Inspires the Brain Metastatic Tumor Targeted Drug Delivery,Molecular Pharmaceutics

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Structure Reconstruction of LyP-1: Lc(LyP-1) Coupling by Amide Bond Inspires the Brain Metastatic Tumor Targeted Drug Delivery
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2017-12-22 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00801
Xiaoyu Zhang _{1,

2} , Fei Wang _{1,

2} , Qing Shen _{1,

2} , Cao Xie _{1,

2} , Yu Liu _{1,

2} , Jun Pan _{1,

2} , Weiyue Lu _{1,

2,

3,

4}

Affiliation

The stability and binding affinity of targeting ligands are very important in active targeting drug delivery. Herein we used LyP-1 peptide as a model peptide to investigate chemical–biology-based strategies in the design of peptide ligands for active targeting. LyP-1 is a short peptide cyclized with a disulfide bond. It can specifically bind to tumor cells and tumor lymphatics through the interaction with cell-surface protein p32/gC1qR. ^Lc(LyP-1), with a same sequence of LyP-1, is coupled by amide bond. It showed better cellular uptake and stability in blood in our previous research. Further, usually d-peptide demonstrates higher stability than l-peptide, and it may contribute to better active targeting ability in vivo. Herein, we designed a retro-inverso isomer of ^Lc(LyP-1), termed ^Dc(LyP-1), expecting to inspire brain metastatic tumor targeted drug delivery. However, although ^Lc(LyP-1) showed lower stability than ^Dc(LyP-1) in fresh rat bold serum, both the 4T1 cellular uptake capacity (89.20%) and p32 protein binding affinity (7.39 × 10^–6) were significantly higher than those (33.41%, 1.37 × 10^–5) of ^Dc(LyP-1). Further, ^Lc(LyP-1) modified PEG–PLA micelles displayed much higher in vivo distribution in brain metastatic tumor than ^Dc(LyP-1). All results suggested that ^Lc(LyP-1) had a better performance than ^Dc(LyP-1) in brain metastatic tumor-targeted drug delivery.

中文翻译：

酰胺键对LyP-1：^L c（LyP-1）偶联的结构重建激发了脑转移肿瘤靶向药物的传递。

靶向配体的稳定性和结合亲和力在主动靶向药物递送中非常重要。在本文中，我们使用LyP-1肽作为模型肽，以研究基于化学生物学的策略设计主动靶向肽配体。LyP-1是用二硫键环化的短肽。通过与细胞表面蛋白p32 / gC1qR的相互作用，它可以与肿瘤细胞和淋巴管特异性结合。^具有LyP-1相同序列的^L c（LyP-1）通过酰胺键偶联。在我们之前的研究中，它显示出更好的细胞摄取和血液中的稳定性。此外，通常d肽表现出比l肽更高的稳定性，并且可能有助于体内更好的主动靶向能力。在这里，我们设计了^L c（LyP-1）的逆向异构体，称为^D c（LyP-1），期望激发脑转移性肿瘤靶向药物的传递。但是，尽管在新鲜大鼠粗体血清中^L c（LyP-1）的稳定性低于^D c（LyP-1），但4T1细胞的摄取能力（89.20％）和p32蛋白结合亲和力（7.39×10 ^–6）均是比显著更高（33.41％，1.37×10 ^-5的）^d C（LYP-1）。此外，^L c（LyP-1）修饰的PEG-PLA胶束在脑转移性肿瘤中的体内分布比^D c（LyP-1）高得多。所有结果表明，^Lc（LyP-1）在脑转移性肿瘤靶向药物输送中的性能优于^D c（LyP-1）。

更新日期：2017-12-22

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