A Tumor-Homing Peptide Platform Enhances Drug Solubility, Improves Blood-Brain Barrier Permeability and Targets Glioblastoma.
A Tumor-Homing Peptide Platform Enhances Drug Solubility, Improves Blood-Brain Barrier Permeability and Targets Glioblastoma.
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DOI：
10.3390/cancers14092207
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发表时间：
2022-04-28
期刊：
影响因子：
5.2
通讯作者：
Lawler, Sean E.
中科院分区：
文献类型：
--
作者：
Cho, Choi-Fong;Farquhar, Charlotte E.;Fadzen, Colin M.;Scott, Benjamin;Zhuang, Pei;von Spreckelsen, Niklas;Loas, Andrei;Hartrampf, Nina;Pentelute, Bradley L.;Lawler, Sean E.
胶质母细胞瘤(GBM)是一种致命的、不可治愈的脑癌，目前的治疗方案显示出有限的成功。这里，我们描述了具有BBB穿透特性和靶向GBM的DG-BCAN靶向多肽(BTP-7)的用途。将BTP-7与不溶性抗癌药物喜树碱(CPT)偶联，可改善药物在水溶液中的溶解度，保持对患者来源的GBM干细胞(GSC)的药效，增强血脑屏障的通透性，并能够靶向治疗小鼠颅内患者来源的GBM异种移植，导致与正常脑组织相比，GBM细胞的毒性更高，并延长动物存活时间。这项工作证明了BTP-7作为一种肿瘤靶向性多肽用于治疗GBM的概念验证。背景：胶质母细胞瘤(GBM)是最常见和最致命的原发脑肿瘤，在患者中具有显著的发病率和死亡率。由于目前的护理标准显示出有限的成功，迫切需要开发新的有效的GBM疗法。推进GBM化疗的主要挑战包括生物利用度低、缺乏肿瘤选择性导致不良副作用、血脑屏障(BBB)通透性差以及肿瘤内广泛的异质性。方法：我们先前已经确定了一种能够穿过血脑屏障并靶向人GBM细胞外基质(ECM)的小分子可溶性多肽(BTP-7)。在这里，我们将BTP-7共价连接到难溶的抗癌药物喜树碱(CPT)上。结果：我们证明，BTP-7与CPT的偶联改善了药物在水溶液中的溶解度，保持了对患者来源的GBM干细胞(GSC)的药物效力，增强了血脑屏障的通透性，并能够针对颅内GBM进行治疗，导致与正常脑组织相比，GBM细胞的毒性更高，最终延长了携带患者来源的GBM异种移植的小鼠的存活时间。结论：BTP-7是一种新的治疗方法，它为GBM靶向治疗方法的可能性打开了大门。
Glioblastoma (GBM) is a fatal and incurable brain cancer, and current treatment options have demonstrated limited success. Here, we describe the use of a dg-Bcan-Targeting-Peptide (BTP-7) that has BBB-penetrating properties and targets GBM. Conjugation of BTP-7 to an insoluble anti-cancer drug, camptothecin (CPT), improves drug solubility in aqueous solution, retains drug efficacy against patient-derived GBM stem cells (GSC), enhances BBB permeability, and enables therapeutic targeting to intracranial patient-derived GBM xenograft in mice, leading to higher toxicity in GBM cells compared to normal brain tissues and prolonged animal survival. This work demonstrates a proof-of-concept for BTP-7 as a tumor-targeting peptide for therapeutic delivery to GBM. Background: Glioblastoma (GBM) is the most common and deadliest malignant primary brain tumor, contributing significant morbidity and mortality among patients. As current standard-of-care demonstrates limited success, the development of new efficacious GBM therapeutics is urgently needed. Major challenges in advancing GBM chemotherapy include poor bioavailability, lack of tumor selectivity leading to undesired side effects, poor permeability across the blood–brain barrier (BBB), and extensive intratumoral heterogeneity. Methods: We have previously identified a small, soluble peptide (BTP-7) that is able to cross the BBB and target the human GBM extracellular matrix (ECM). Here, we covalently attached BTP-7 to an insoluble anti-cancer drug, camptothecin (CPT). Results: We demonstrate that conjugation of BTP-7 to CPT improves drug solubility in aqueous solution, retains drug efficacy against patient-derived GBM stem cells (GSC), enhances BBB permeability, and enables therapeutic targeting to intracranial GBM, leading to higher toxicity in GBM cells compared to normal brain tissues, and ultimately prolongs survival in mice bearing intracranial patient-derived GBM xenograft. Conclusion: BTP-7 is a new modality that opens the door to possibilities for GBM-targeted therapeutic approaches.
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DOI：
10.2147/dddt.s135571
发表时间：
2017
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Kalim M;Chen J;Wang S;Lin C;Ullah S;Liang K;Ding Q;Chen S;Zhan J
通讯作者：
Zhan J
DOI：
10.1083/jcb.125.2.495
发表时间：
1994-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Jaworski DM;Kelly GM;Hockfield S
通讯作者：
Hockfield S
影响因子：
4.7
作者：
Gupta K;Burns TC
通讯作者：
Burns TC
影响因子：
11.2
作者：
Morgan, Meredith T.;Nakanishi, Yuka;Grinstaff, Mark W.
通讯作者：
Grinstaff, Mark W.
影响因子：
2.7
作者：
Henne, Walter A.;Doorneweerd, Derek D.;Low, Philip S.
通讯作者：
Low, Philip S.