Dual Receptor Recognizing Cell Penetrating Peptide for Selective Targeting, Efficient Intratumoral Diffusion and Synthesized Anti-Glioma Therapy.
Dual Receptor Recognizing Cell Penetrating Peptide for Selective Targeting, Efficient Intratumoral Diffusion and Synthesized Anti-Glioma Therapy.
复制标题
双受体识别细胞穿透肽，用于选择性靶向、高效瘤内扩散和合成抗神经胶质瘤治疗
作者：
Liu Y;Mei L;Xu C;Yu Q;Shi K;Zhang L;Wang Y;Zhang Q;Gao H;Zhang Z;He Q
细胞穿透肽(CPPs)被广泛用于肿瘤的药物传递。然而，非选择性的体内渗透极大地限制了CPPS介导的药物传递系统的应用。而恶性肿瘤的治疗往往因肿瘤血管外核心区的存在而导致预后不良和复发。因此，赋予CPPs选择性靶向和更强的肿瘤内扩散能力是重要的。在本研究中，将RGD反向序列DGR与CpP 8-精氨酸偶联，形成一个含有串联多肽R8-DGR的CendR(R/KXXR/K)基序(RRRRRRRDGR)，该基序可与整合素αvβ3和Neu Pilin-1受体结合。双受体识别肽R8-DGR在体外表现出细胞摄取增加和对胶质瘤球体的有效穿透能力。以下体内研究表明，R8-DGR修饰脂质体具有主动靶向性和瘤内扩散能力。将紫杉醇负载到脂质体中，PTX-R8-DGR-Lip在体外对肿瘤细胞和肿瘤干细胞均有最强的抗增殖作用，并抑制血管生成拟态通道的形成。最后，R8-DGR脂质体给药系统使C6荷瘤小鼠的中位存活时间比未治疗组延长了2.1倍，并实现了包括抗肿瘤细胞、抗血管生成拟态和抗脑肿瘤干细胞在内的彻底的抗胶质瘤治疗。综上所述，R8-DGR是一种理想的识别CPP的双重受体，具有选择性的肿瘤靶向性和有效的瘤内扩散，可进一步用于装备药物输送系统进行有效的脑胶质瘤治疗。
Cell penetrating peptides (CPPs) were widely used for drug delivery to tumor. However, the nonselective in vivo penetration greatly limited the application of CPPs-mediated drug delivery systems. And the treatment of malignant tumors is usually followed by poor prognosis and relapse due to the existence of extravascular core regions of tumor. Thus it is important to endue selective targeting and stronger intratumoral diffusion abilities to CPPs. In this study, an RGD reverse sequence dGR was conjugated to a CPP octa-arginine to form a CendR (R/KXXR/K) motif contained tandem peptide R8-dGR (RRRRRRRRdGR) which could bind to both integrin αvβ3 and neuropilin-1 receptors. The dual receptor recognizing peptide R8-dGR displayed increased cellular uptake and efficient penetration ability into glioma spheroids in vitro. The following in vivo studies indicated the active targeting and intratumoral diffusion capabilities of R8-dGR modified liposomes. When paclitaxel was loaded in the liposomes, PTX-R8-dGR-Lip induced the strongest anti-proliferation effect on both tumor cells and cancer stem cells, and inhibited the formation of vasculogenic mimicry channels in vitro. Finally, the R8-dGR liposomal drug delivery system prolonged the medium survival time of intracranial C6 bearing mice by 2.1-fold compared to the untreated group, and achieved an exhaustive anti-glioma therapy including anti-tumor cells, anti-vasculogenic mimicry and anti-brain cancer stem cells. To sum up, all the results demonstrated that R8-dGR was an ideal dual receptor recognizing CPP with selective glioma targeting and efficient intratumoral diffusion, which could be further used to equip drug delivery system for effective glioma therapy.