Liposome-based glioma targeted drug delivery enabled by stable peptide ligands
Liposome-based glioma targeted drug delivery enabled by stable peptide ligands
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通过稳定的肽配体实现基于脂质体的神经胶质瘤靶向药物递送
DOI：
10.1016/j.jconrel.2015.09.059
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发表时间：
2015-11-28
影响因子：
10.8
通讯作者：
Lu, Weiyue
中科院分区：
文献类型：
--
作者：
Wei, Xiaoli;Gao, Jie;Lu, Weiyue
胶质瘤的治疗是临床上最具挑战性的任务之一。作为一种颅内肿瘤，神经胶质瘤表现出许多与其他肿瘤不同的特征。特别是，各种屏障，包括血液和脑毛细血管内皮细胞中的酶屏障、血脑屏障（BBB）和血脑肿瘤屏障（BBTB）严格阻止药物和药物递送系统到达肿瘤部位。为了解决这一困境，我们开发了一种脂质体制剂，通过用蛋白水解稳定的肽、(CDX)-C-D 和 c(RGDyK) 修饰脂质体表面来规避多重屏障。 (CDX)-C-D 是 BBB 上尼古丁乙酰胆碱受体 (nAChR) 的 D 肽配体，c(RGDyK) 是在 BBTB 和神经胶质瘤细胞上高度表达的整合素配体。脑毛细血管内皮细胞的溶酶体区室参与这些脂质体的转胞吞作用。然而，两种肽配体在溶酶体匀浆中表现出异常的稳定性，确保完整的配体可以发挥脑毛细血管内皮细胞和神经胶质瘤靶向的后续胞吐作用。在细胞摄取研究中，双标记脂质体可以同时靶向脑毛细血管内皮细胞和肿瘤细胞，有效穿过BBB和BBTB单层，克服酶屏障并靶向三维肿瘤球体。其对颅内神经胶质瘤的靶向能力通过离体成像和组织学研究在体内得到进一步验证。结果，与未修饰的脂质体和用单独的肽配体修饰的脂质体相比，用(CDX)-C-D和c(RGDyK)修饰的阿霉素脂质体表现出更好的抗神经胶质瘤效果，延长了患有神经胶质瘤的裸鼠的中位生存期。总之，本研究提出的脂质体可以有效克服多重障碍，实现胶质瘤靶向给药，验证了其在提高阿霉素治疗胶质瘤疗效方面的潜在价值。 (C) 2015 Elsevier B.V. 保留所有权利。
The treatment of glioma is one of the most challenging tasks in clinic. As an intracranial tumor, glioma exhibits many distinctive characteristics from other tumors. In particular, various barriers including enzymatic barriers in the blood and brain capillary endothelial cells, blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) rigorously prevent drug and drug delivery systems from reaching the tumor site. To tackle this dilemma, we developed a liposomal formulation to circumvent multiple-barriers by modifying the liposome surface with proteolytically stable peptides, (CDX)-C-D and c(RGDyK). (CDX)-C-D is a D-peptide ligand of nicotine acetylcholine receptors (nAChRs) on the BBB, and c(RGDyK) is a ligand of integrin highly expressed on the BBTB and glioma cells. Lysosomal compartments of brain capillary endothelial cells are implicated in the transcytosis of those liposomes. However, both peptide ligands displayed exceptional stability in lysosomal homogenate, ensuring that intact ligands could exert subsequent exocytosis from brain capillary endothelial cells and glioma targeting. In the cellular uptake studies, dually labeled liposomes could target both brain capillary endothelial cells and tumor cells, effectively traversing the BBB and BBTB monolayers, overcoming enzymatic barrier and targeting three-dimensional tumor spheroids. Its targeting ability to intracranial glioma was further verified in vivo by ex vivo imaging and histological studies. As a result, doxorubicin liposomes modified with both (CDX)-C-D and c(RGDyK) presented better anti-glioma effect with prolonged median survival of nude mice bearing glioma than did unmodified liposomes and liposomes modified with individual peptide ligand. In conclusion, the liposome suggested in the present study could effectively overcome multi-barriers and accomplish glioma targeted drug delivery, validating its potential value in improving the therapeutic efficacy of doxorubicin for glioma. (C) 2015 Elsevier B.V. All rights reserved.