Department of Pharmaceutics, School of Pharmacy , Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA , Shanghai 201203 , China.
State Key Laboratory of Medical Neurobiology, and Collaborative Innovation Center for Brain Science , Fudan University , Shanghai 200032 , China.
ACS Appl Mater Interfaces. 2018 Jun 13;10(23):19473-19482. doi: 10.1021/acsami.8b05235. Epub 2018 Jun 1.
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. The A7R peptide has effective BBTB-penetrating and notable glioma-, angiogenesis-, and VM-targeting abilities. Herein, we designed a myristic acid modified A7R ligand (MC-A7R), which combines tumor-homing A7R with BBB-penetrable MC. MC-A7R was then immobilized to PEGylated liposomes (MC-A7R-LS) to form a whole-process glioma-targeting system. MC-A7R-LS exhibited exceptional internalization in glioma, tumor neovascular, and brain capillary endothelial cells. Enhanced BBTB- and BBB-traversing efficiencies were also observed on MC-A7R-LS. Ex vivo imaging on brain tumors also demonstrated the feasibility of MC-A7R-LS in intracranial glioma-homing, whereas the immunofluorescence studies demonstrated its GSC and angiogenesis homing. Furthermore, doxorubicin-loaded MC-A7R-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-modified A7R peptide as a great candidate for the whole-process glioma-targeted drug delivery.
侵袭性神经胶质瘤的临床治疗一直是一个巨大的挑战，主要是由于神经胶质瘤微环境的复杂性以及血脑肿瘤屏障（BBTB）/血脑屏障（BBB）的存在，这严重阻碍了大多数治疗药物在神经胶质瘤区域的有效积累。此外，恶性神经胶质瘤中的血管生成拟态（VM）、血管生成和神经胶质瘤干细胞（GSC）也导致临床治疗失败。为了解决上述问题，提出了一种全过程神经胶质瘤靶向药物递送策略。A7R 肽具有有效的 BBTB 穿透能力和显著的神经胶质瘤、血管生成和 VM 靶向能力。在这里，我们设计了一种豆蔻酸修饰的 A7R 配体（MC-A7R），它将肿瘤归巢的 A7R 与可穿透 BBB 的 MC 结合在一起。然后，将 MC-A7R 固定到聚乙二醇化脂质体（MC-A7R-LS）上，形成一个全过程神经胶质瘤靶向系统。MC-A7R-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优异的内化作用。还观察到 MC-A7R-LS 具有增强的 BBTB 和 BBB 穿透效率。脑肿瘤的离体成像也证明了 MC-A7R-LS 在颅内神经胶质瘤归巢的可行性，而免疫荧光研究则证明了其 GSC 和血管生成归巢。此外，载多柔比星的 MC-A7R-LS 由于协同改善神经胶质瘤微环境，取得了显著的治疗效果。我们的研究强调了 MC 修饰的 A7R 肽作为全过程神经胶质瘤靶向药物递送的潜在应用。
