Ran Danni, Zhou Jianfen, Chai Zhilan, Li Jinyang, Xie Cao, Mao Jiani, Lu Linwei, Zhang Yanyu, Wu Sunyi, Zhan Changyou, Lu Weiyue
Department of Pharmaceutics, School of Pharmacy, Fudan University, and Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, & State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Department of Integrative Medicine, Huashan Hospital, and Institutes of Integrative Medicine of Fudan University, Shanghai 200041, China.
Theranostics. 2020 Mar 4;10(9):4073-4087. doi: 10.7150/thno.41382. eCollection 2020.
Uncontrollable cell proliferation and irreversible neurological damage make glioma one of the most deadly diseases in clinic. Besides the multiple biological barriers, glioma stem cells (GSCs) that are responsible for the maintenance and recurrence of tumor tissues also hinder the therapeutic efficacy of chemotherapy. Therefore, all-stage precisional glioma targeted therapy regimens that could efficiently deliver drugs to glioma cells and GSCs after overcoming multiple barriers have received increasing scrutiny. : A polymeric micelle-based drug delivery system was developed by modifying a "Y-shaped" well-designed ligand of both GRP78 protein and quorum sensing receptor to achieve all-stage precisional glioma targeting, then we evaluated the targeting ability and barrier penetration ability both and . In order to achieve all-stage precisional therapy, we need kill both GSCs and glioma related cells. Parthenolide (PTL) has been investigated for its selective toxicity to glioma stem cells while Paclitaxel (PTX) and Temozolomide (TMZ) are widely used in experimental and clinical therapy of glioma respectively. So the anti-glioma effect of combination therapy was evaluated by Kaplan-Meier survival analysis and immunohistochemical (IHC) examination of tumor tissues. : The "Y-shaped" well-designed peptide, termed WVAP, exhibited excellent glioma (and GSCs) homing and barrier penetration ability. When modified on micelle surface, WVAP peptide significantly enhanced accumulation of micelles in brain and glioma. In addition, WVAP micelles showed no immunogenicity and cytotoxicity, which could guarantee their safety when used . Treatment of glioma-bearing mice with PTL loaded WVAP modified PEG-PLA micelles plus PTX loaded WVAP modified PEG-PLA micelles or PTL loaded WVAP modified PEG-PLA micelles plus TMZ showed improved anti-tumor efficacy in comparison to PTL and PTX loaded unmodified micelles or PTL loaded unmodified micelles plus TMZ. : Combination of all-stage targeting strategy and concomitant use of chemotherapeutics and stem cell inhibitors could achieve precise targeted therapy for glioma.
无法控制的细胞增殖和不可逆的神经损伤使胶质瘤成为临床上最致命的疾病之一。除了多种生物屏障外，负责肿瘤组织维持和复发的胶质瘤干细胞（GSCs）也阻碍了化疗的治疗效果。因此，能够在克服多种屏障后将药物有效递送至胶质瘤细胞和GSCs的全阶段精准胶质瘤靶向治疗方案受到了越来越多的关注。：通过修饰GRP78蛋白和群体感应受体的“Y形”精心设计的配体，开发了一种基于聚合物胶束的药物递送系统，以实现全阶段精准胶质瘤靶向，然后我们评估了其靶向能力和屏障穿透能力。为了实现全阶段精准治疗，我们需要杀死GSCs和胶质瘤相关细胞。已研究了小白菊内酯（PTL）对胶质瘤干细胞的选择性毒性，而紫杉醇（PTX）和替莫唑胺（TMZ）分别广泛用于胶质瘤的实验和临床治疗。因此，通过Kaplan-Meier生存分析和肿瘤组织的免疫组织化学（IHC）检查评估了联合治疗的抗胶质瘤效果。：精心设计的“Y形”肽，称为WVAP，表现出优异的胶质瘤（和GSCs）归巢和屏障穿透能力。当修饰在胶束表面时，WVAP肽显著增强了胶束在脑和胶质瘤中的积累。此外，WVAP胶束没有免疫原性和细胞毒性，这可以保证其使用时的安全性。与负载PTL和PTX的未修饰胶束或负载PTL的未修饰胶束加TMZ相比，用负载PTL的WVAP修饰的PEG-PLA胶束加负载PTX的WVAP修饰的PEG-PLA胶束或负载PTL的WVAP修饰的PEG-PLA胶束加TMZ治疗荷瘤小鼠显示出改善的抗肿瘤效果。：全阶段靶向策略与化疗药物和干细胞抑制剂的联合使用可以实现对胶质瘤的精准靶向治疗。
