Abstract

Glioblastoma (GBM) is an aggressive malignancy and therapeutic options are limited due to the presence of the blood–brain barrier (BBB). RVG-29, a 29-amino-acid polypeptide derived from the rabies virus glycoprotein (RVG), has excellent brain-targeted capacity across the BBB. We reduced the size of this peptide to get a15-amino-acid polypeptide (RVG-15), while retaining its brain-targeted capacity across the BBB. First, we synthesized a novel nanocarrier RVG-15-PEG₂₀₀₀-DSPE. Next, DOX-loaded polymeric micelles (DOX RVG-15-PMs) were prepared in an electrostatic interaction-dependent manner. Finally, we evaluated its antitumor benefits in vitro at the cellular level and in vivo using an in situ tumour-bearing mouse model. MALDI-TOF-MS and FTIR spectra confirmed the successful synthesis of the novel nanocarrier. The prepared DOX RVG-15-PMs displayed even size distribution, a high entrapment efficiency and satisfactory in vitro release behaviour. In vitro blank RVG-15-PMs were excellent, safe and highly biocompatible as drug delivery carriers. DOX-loaded micelles were easily taken up by C6 cells and could effectively inhibit cancer development and metastasis. In vivo, DOX RVG-15-PMs delayed weight loss, prevented cancer cell metastasis and accelerated cancer cell apoptosis in tumour-bearing mice. Our novel brain-targeted nanocarrier is highly feasible, while DOX RVG-15-PMs exert significant antiglioma effects, both in vitro and in vivo.

摘要

胶质母细胞瘤 (GBM) 是一种侵袭性恶性肿瘤，由于存在血脑屏障 (BBB)，治疗选择受到限制。RVG-29 是一种源自狂犬病病毒糖蛋白 (RVG) 的 29 个氨基酸的多肽，在 BBB 中具有出色的脑靶向能力。我们减小了这种肽的大小以获得 15 个氨基酸多肽 (RVG-15)，同时保留其在 BBB 中的脑靶向能力。首先，我们合成了一种新型纳米载体RVG-15-PEG ₂₀₀₀ -DSPE。接下来，以静电相互作用依赖的方式制备了负载 DOX 的聚合物胶束 (DOX RVG-15-PMs)。最后，我们使用原位在细胞水平和体内评估了其体外抗肿瘤益处荷瘤小鼠模型。MALDI-TOF-MS 和 FTIR 光谱证实了新型纳米载体的成功合成。制备的 DOX RVG-15-PMs 显示出均匀的尺寸分布、较高的包封率和令人满意的体外释放行为。体外空白 RVG-15-PMs 作为药物递送载体具有优异、安全和高度生物相容性。载有 DOX 的胶束容易被 C6 细胞吸收，可有效抑制癌症的发展和转移。在体内，DOX RVG-15-PMs 在荷瘤小鼠中延缓体重减轻、阻止癌细胞转移并加速癌细胞凋亡。我们的新型脑靶向纳米载体非常可行，而 DOX RVG-15-PM在体外均发挥显着的抗神经胶质瘤作用和体内。