CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels
CGKRK-modified nanoparticles for dual-targeting drug delivery to tumor cells and angiogenic blood vessels
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CGKRK 修饰纳米颗粒用于双靶向药物递送至肿瘤细胞和血管生成血管
DOI：
10.1016/j.biomaterials.2013.09.001
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发表时间：
2013-12-01
期刊：
影响因子：
14
通讯作者：
Chen, Jun
中科院分区：
文献类型：
--
作者：
Hu, Quanyin;Gao, Xiaoling;Chen, Jun
抗血管生成治疗在临床肿瘤治疗中显示出巨大的优势，但尚未达到总生存率。这些折衷的结果主要是由于固有的/获得性的抗血管生成药物耐药性和抗血管生成治疗后局部侵袭或远处转移的增加所致。在这里，我们构建了CGKRK多肽修饰的聚乙二醇共PCL纳米粒药物传递系统(DDS)，旨在同时靶向肿瘤血管生成和肿瘤细胞，以达到增强抗肿瘤活性的目的，并具有克服单一抗血管生成治疗的缺点的巨大潜力。所获得的CGKRK功能化聚乙二醇共PCL纳米粒(CGKRK-NP)的粒径为117.28+/-10.42 nm，zeta电位为-15.7+/-3.32 mV，在人脐静脉内皮细胞上表现出能量依赖性的脂筏/小窝介导的内吞作用和人U87 MG细胞的能量依赖性脂筏/小窝介导的内吞作用。以香豆素-6为荧光探针，体外U87 MG肿瘤球体检测表明，CGKRK-NP能有效地穿透肿瘤球体。体内成像和肿瘤切片分析证实CGKRK-NP在肿瘤部位有选择性聚集和广泛的生物分布。载药后，CGKRK-NP增强了载药PTX对HUVEC细胞和U87 MG细胞的杀伤和诱导凋亡活性，并增强了其对U87 MG肿瘤球体生长的抑制作用。PTX-CGKRK-NP治疗后，皮下U87 MG肿瘤小鼠的肿瘤体积最小。本研究结果表明，CGKRK多肽功能化纳米颗粒DDS可作为一种有效的肿瘤血管生成血管和肿瘤细胞双靶向DDS，为减少单纯抗血管生成治疗的缺点提供了一条很有前途的途径。(C)2013爱思唯尔有限公司。保留所有权利。
Antiangiogenic therapy shows great advantages in clinical cancer treatment while no overall survival has been achieved. The compromised results were mainly contributed by intrinsic/acquired antiangiogenic drug resistance and increased local invasion or distant metastasis after antiangiogenic therapy. Here we constructed a CGKRK peptide-modified PEG-co-PCL nanoparticulate drug delivery system (DDS), aiming at targeting both tumor angiogenic blood vessels and tumor cells to achieve enhanced anti-tumor activity as well as holding a great potential to overcome the drawbacks of antiangiogenic therapy alone. The obtained CGKRK-functionalized PEG-co-PCL nanoparticles (CGKRK-NP) with a particle size of 117.28 +/- 10.42 nm and zeta potential of -15.7 +/- 3.32 mV, exhibited an enhanced accumulation via an energy-dependent, lipid raft/caveolae-mediated endocytosis with the involvement of microtubules in human umbilical vein endothelial cells (HUVEC) and an energy-dependent, lipid raft/caveolae-mediated endocytosis with the participation of Golgi apparatus in human U87MG cells. Using coumarin-6 as the fluorescence probe, in vitro U87MG tumor spheroids assays showed that CGKRK-NP effectively penetrated into the tumor spheroids. Selective accumulation and extensive bio-distribution of CGKRK-NP at tumor site was confirmed by in vivo imaging and tumor section analysis. After drug loading, CGKRK-NP enhanced cytotoxicity and apoptosis induction activity of the loaded PTX on both HUVEC cells and U87MG cells and improved its inhibition effect on the growth of U87MG tumor spheroids. The smallest tumor volume was achieved by those mice bearing subcutaneous U87MG tumor following the treatment of PTX-loaded CGKRK-NP. The findings' here indicated that CGKRK peptide-functionalized nanoparticulate DDS could be used as an effective tumor angiogenic blood vessels and tumor cells dual-targeting DDS and might provide a great promising approach for reducing the disadvantages of antiangiogenic therapy alone. (C) 2013 Elsevier Ltd. All rights reserved.