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Tumor-penetrating peptide functionalization enhances the anti-glioblastoma effect of doxorubicin liposomes

机译：穿透肿瘤的肽功能增强阿霉素脂质体的抗胶质母细胞瘤作用

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The targeted therapeutic effect of nano drug delivery system for glioblastoma has been hampered by the weak enhanced permeability and retention (EPR) effect of glioblastoma and the low delivering efficiency of NDDS in glioblastoma tissue. In this study, a tumor-penetrating peptide (RGERPPR), the specific ligand of neuropilin-1 overexpressed on glioblastoma and endothelial cells, was used as a targeting moiety to enhance the anti-glioblastoma effect of doxorubicin liposomes. Firstly, RGERPPR-PEG-DSPE was synthesized and used to prepare the RGERPPR peptide-functionalized liposomes (RGE-LS), which showed vesicle sizes of around 90 nm and narrow size distributions. The cellular uptake and in vivo near-infrared fluorescence imaging test displayed that RGE-LS exhibited increased uptake by glioblastoma cells and intracranial glioblastoma tissues. The cytotoxicity assay and anti-glioblastoma study proved that RGERPPR functionalization significantly enhanced the in vitro inhibitory effect of doxorubicin liposomes on glioblastoma cells and prolonged the median survival time of nude mice bearing intracranial glioblastoma. Finally, the immunofluorescence analysis evidenced that RGE-LS were able to penetrate through tumor vessels and stroma and deep into the whole tumor tissue. The results indicated that tumor-penetrating peptide functionalization is an effective strategy for enhancing the anti-glioblastoma effect of doxorubicin liposomes.
机译：胶质母细胞瘤的增强的渗透性和保留（EPR）效果较弱，胶质母细胞瘤组织中的NDDS传递效率低，阻碍了纳米药物递送系统对胶质母细胞瘤的靶向治疗效果。在这项研究中，肿瘤穿透肽（RGERPPR）（在胶质母细胞瘤和内皮细胞中过表达的Neuropilin-1的特异性配体）被用作靶向部分，以增强阿霉素脂质体的抗胶质母细胞瘤作用。首先，合成了RGERPPR-PEG-DSPE，并用于制备RGERPPR肽官能化脂质体（RGE-LS），该脂质体的囊泡大小约为90 nm，粒径分布较窄。细胞摄取和体内近红外荧光成像测试显示，RGE-LS表现出胶质母细胞瘤细胞和颅内胶质母细胞瘤组织摄取增加。细胞毒性试验和抗成胶质细胞母细胞瘤的研究证明，RGERPPR功能显着增强了阿霉素脂质体对成胶质细胞瘤细胞的体外抑制作用，并延长了患有颅内成胶质细胞瘤的裸鼠的中位生存时间。最后，免疫荧光分析证明RGE-LS能够穿透肿瘤血管和间质并深入整个肿瘤组织。结果表明，穿透肿瘤的肽功能化是增强阿霉素脂质体的抗成胶质细胞瘤作用的有效策略。

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