Myristic Acid-Modified (D)A7R Peptide for Whole-Process Glioma-Targeted Drug Delivery
Myristic Acid-Modified (D)A7R Peptide for Whole-Process Glioma-Targeted Drug Delivery
复制标题
用于胶质瘤靶向药物全程递送的肉豆蔻酸修饰 (D)A7R 肽
DOI：
10.1021/acsami.8b05235
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发表时间：
2018
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;Wang Songli;Zhang Mingfei;Wang Ruifeng;Zhu Hangchang;Ruan Huitong;Ran Danni;Chai Zhilan;Wang Xiaoyi;Lu Weiyue
侵袭性胶质瘤的临床治疗一直是一个巨大的挑战，主要是由于胶质瘤微环境的复杂性和血脑肿瘤屏障（BBTB）/血脑屏障（BBB）的存在，严重阻碍了大多数治疗药物在胶质瘤区域的有效蓄积。此外，恶性胶质瘤中的血管生成拟态（VM）、血管生成和胶质瘤干细胞（GSC）也导致临床治疗失败。针对上述问题，提出了胶质瘤全程靶向给药策略。DA 7 R肽具有有效的BBBB穿透和显著的胶质瘤、血管生成和VM靶向能力。在此，我们设计了一种肉豆蔻酸修饰的DA 7 R配体（MC-DA 7 R），其将肿瘤归巢的DA 7 R与BBB可穿透的MC结合。然后将MC-DA 7 R固定于PEG化脂质体（MC-DA 7 R-LS）上，形成胶质瘤全程靶向系统。MC-DA 7 R-LS在神经胶质瘤、肿瘤新生血管和脑毛细血管内皮细胞中表现出异常的内化。在MC-DA 7 R-LS上也观察到增强的BBTB-和BBB-穿越效率。对脑肿瘤的离体成像也证明了MC-DA 7 R-LS在颅内胶质瘤归巢中的可行性，而免疫荧光研究证明了其GSC和血管生成归巢。此外，由于对神经胶质瘤微环境的协同改善，负载阿霉素的MC-DA 7 R-LS实现了显著的治疗结果。我们的研究突出了MC修饰的DA 7 R肽作为全过程胶质瘤靶向药物递送的伟大候选者的潜力。
The clinical treatment of aggressive glioma has been a great challenge, mainly because of the complexity of the glioma microenvironment and the existence of the blood–brain tumor barrier (BBTB)/blood–brain barrier (BBB), which severely hampers the effective accumulation of most therapeutic agents in the glioma region. Additionally, vasculogenic mimicry (VM), angiogenesis, and glioma stem cells (GSC) in malignant glioma also lead to the failure of clinical therapy. To address the aforementioned issues, a whole-process glioma-targeted drug delivery strategy was proposed. TheDA7R peptide has effective BBTB-penetrating and notable glioma-, angiogenesis-, and VM-targeting abilities. Herein, we designed a myristic acid modifiedDA7R ligand (MC-DA7R), which combines tumor-homingDA7R with BBB-penetrable MC. MC-DA7R was then immobilized to PEGylated liposomes (MC-DA7R-LS) to form a whole-process glioma-targeting system. MC-DA7R-LS exhibited exceptional internalization in glioma, tumor neovascular, and brain capillary endothelial cells. Enhanced BBTB- and BBB-traversing efficiencies were also observed on MC-DA7R-LS. Ex vivo imaging on brain tumors also demonstrated the feasibility of MC-DA7R-LS in intracranial glioma-homing, whereas the immunofluorescence studies demonstrated its GSC and angiogenesis homing. Furthermore, doxorubicin-loaded MC-DA7R-LS accomplished a remarkable therapeutic outcome, as a result of a synergistic improvement on the glioma microenvironment. Our study highlights the potential of the MC-modifiedDA7R peptide as a great candidate for the whole-process glioma-targeted drug delivery.