Liposome-Based Systemic Glioma-Targeted Drug Delivery Enabled by All-D Peptides
Liposome-Based Systemic Glioma-Targeted Drug Delivery Enabled by All-D Peptides
复制标题
All-D 肽实现基于脂质体的系统性胶质瘤靶向药物递送
DOI：
10.1021/acsami.6b10146
复制
发表时间：
2016-11-09
影响因子：
9.5
通讯作者：
Lu, Weiyue
中科院分区：
文献类型：
--
作者：
Ying, Man;Zhan, Changyou;Lu, Weiyue
恶性胶质瘤是脑肿瘤中最具侵袭性的一种肿瘤，其化疗在临床上仍极具挑战性。血脑屏障（BBB）和血脑肿瘤屏障（BBTB）是阻止治疗药物到达胶质瘤区域的生理和病理屏障。此外，胶质瘤中侵袭性胶质瘤细胞形成的血管生成模拟（vascular - genic mimicry， VM），而非内皮细胞和血管生成，在胶质瘤中非常常见，导致胶质瘤预后差，容易复发。理想的胶质瘤化疗药物传递系统需要穿过血脑屏障和血脑屏障，然后靶向VM、血管生成和胶质瘤细胞。在此，我们开发了一种基于脂质体的药物递送系统，该系统通过蛋白水解稳定的D肽配体(（CDX)-C-D/(D)A7R-LS）进行修饰。（CDX）-C-D是尼古丁乙酰胆碱受体（nAChRs）的D肽配体，能够绕过血脑屏障，(D)A7R是血管内皮生长因子受体2 （VEGFR2）和神经匹林-1 （NRP-1）的D肽配体，在血管生成、VM和胶质瘤中过表达，具有良好的胶质瘤归巢性。（CDX）-C-D/(D)A7R-LS能有效内化到脑毛细血管内皮细胞、胶质瘤细胞、肿瘤新生血管内皮细胞和肿瘤球体中，并穿过体外血脑屏障和血脑屏障模型。体外成像和体内免疫荧光实验证实了(CDX)-C-D/(D)A7R- ls在靶向颅内胶质瘤方面的优势，与普通脂质体或由单个D肽配体修饰的脂质体(（CDX)-C-D或(D)A7R）相比。当含有阿霉素时，(CDX)-C-D/(D)A7R-LS在所有测试配方中具有最佳的抗胶质瘤，抗血管生成和抗vm效果。这些结果表明，全d肽配体支持的系统性胶质瘤靶向药物递送在抗胶质瘤治疗中是有希望的。
As the most aggressive brain tumor, chemotherapy of malignant glioma remains to be extremely challenging in clinic. The blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) are physiological and pathological barriers preventing therapeutic drugs from: reaching the glioma region. In addition, vasculogenic mimicry (VM) formed by invasive glioma cells instead of endothelial cells and angiogenesis are very common in glioma, leading to the poor prognosis and recurrence of glioma. An ideal drug delivery system for glioma Chemotherapy needs to traverse the BBB and BBTB and then target VM, angiogenesis, and glioma cells. Herein we developed a liposome-based drug delivery system with the modification of proteolytically stable D-peptide ligands ((CDX)-C-D/(D)A7R-LS). (CDX)-C-D is a D-peptide ligand of nicotine acetylcholine receptors (nAChRs) capable of circumventing the BBB, and (D)A7R is a D-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed on angiogenesis, VM, and glioma, presenting excellent glioma-homing property. (CDX)-C-D/(D)A7R-LS could efficiently internalize into the brain capillary endothelial cells, glioma cells, tumor neovascular endothelial cells, and tumor spheroids and cross the in vitro BBB and BBTB models. Ex vivo imaging and in vivo immunofluorescence assays confirmed the superiority of (CDX)-C-D/(D)A7R-LS in targeting intracranial glioma in comparison to plain liposomes or liposomes modified with an individual D-peptide ligand (either (CDX)-C-D or (D)A7R). When loaded with doxorubicin, (CDX)-C-D/(D)A7R-LS achieved the best antiglioma, antiangiogenesis, and anti-VM effects among all tested formulations. These results suggested that systemic glioma-targeted drug delivery enabled by all-D peptide ligands was promising for the antiglioma therapy.