Drug release kinetics, cell uptake, and tumor toxicity of hybrid VVVVVVKK peptide-assembled polylactide nanoparticles.
Drug release kinetics, cell uptake, and tumor toxicity of hybrid VVVVVVKK peptide-assembled polylactide nanoparticles.
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DOI：
10.1016/j.ejpb.2012.12.012
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发表时间：
2013-05
期刊：
影响因子：
--
通讯作者：
He X
中科院分区：
文献类型：
--
作者：
Jabbari E;Yang X;Moeinzadeh S;He X
一种令人兴奋的肿瘤给药方法是将药物包裹在自组装的聚合物 - 肽纳米粒子中。本研究的目的是合成低分子量聚乳酸（LMW PLA）和V6K2肽的共轭物，并研究其自组装、药物释放动力学、细胞摄取和毒性、药物药代动力学以及阿霉素（DOX）或紫杉醇（PTX）对肿瘤细胞侵袭的影响。将PLA - V6K2自组装纳米粒子的结果与聚乙二醇稳定的PLA（PLA - EG）纳米粒子的结果进行了比较。PLA - V6K2和PLA - EG纳米粒子的尺寸分别为100±20和130±50纳米，多分散指数分别为1.04和1.14。DOX在PLA - V6K2和PLA - EG纳米粒子中的包封率分别为44±9%和55±5%，两种纳米粒子类型对PTX的包封率均>90%。DOX和PTX从PLA - V6K2中的释放比从PLA - EG中释放更慢，且释放速率随时间相对恒定。基于分子动力学模拟，亲水性较强的DOX分布在丙交酯核心以及肽壳中，而疏水性的PTX主要位于丙交酯核心。与PLA - EG纳米粒子相比，PLA - V6K2纳米粒子被4T1小鼠乳腺癌细胞摄取的量显著更高，这归因于肽与细胞膜上带负电荷部分之间的静电相互作用。PLA - V6K2纳米粒子对骨髓基质细胞无毒性。载有DOX的PLA - V6K2纳米粒子对4T1细胞显示出更高的毒性，并且与游离DOX相比，DNA损伤反应和细胞凋亡延迟。与PLA - EG纳米粒子中载药的细胞相比，PLA - V6K2纳米粒子中包裹的DOX或PTX显著降低了4T1细胞的侵袭能力。用PLA - V6K2和PLA - EG纳米粒子载DOX处理的4T1细胞的侵袭率分别为5±1%和30±5%，PTX处理的分别为11±2%和40±7%。PLA - V6K2纳米粒子中DOX的曲线下面积（AUC）分别比游离DOX和PLA - EG纳米粒子高67%和21%。将载有DOX的PLA - V6K2纳米粒子注射到接种了MTCL同基因乳腺癌细胞的C3HeB/FeJ小鼠体内，显示出比PLA - EG纳米粒子更高的肿瘤毒性，且比游离DOX对宿主的毒性更低。具有比PLA - EG纳米粒子更高肿瘤毒性的阳离子PLA - V6K2纳米粒子在化疗中可能具有潜在用途。
An exciting approach to tumor delivery is encapsulation of the drug in self-assembled polymer-peptide nanoparticles. The objective of this work was to synthesize a conjugate of low molecular weight polylactide (LMW PLA) and V6K2 peptide, and investigate self-assembly, drug release kinetics, cell uptake and toxicity, drug pharmacokinetics, and tumor cell invasion with Doxorubicin (DOX) or paclitaxel (PTX). The results for PLA-V6K2 self-assembled NPs were compared with those of polyethylene glycol stabilized PLA (PLA-EG) NPs. The size of PLA-V6K2 and PLA-EG NPs were 100±20 and 130±50 nm, respectively, with polydispersity index of 1.04 and 1.14. The encapsulation efficiency of DOX in PLA-V6K2 and PLA-EG NPs was 44±9% and 55±5%, respectively, and that of PTX was >90 for both NP types. The release of DOX and PTX from PLA-V6K2 was slower than that of PLA-EG and the release rate was relatively constant with time. Based on molecular dynamic simulation, the less hydrophobic DOX was distributed in the lactide core as well as the peptide shell while the hydrophobic PTX was localized mainly to the lactide core. PLA-V6K2 NPs had significantly higher cell uptake by 4T1 mouse breast carcinoma cells compared to PLA-EG NPs, which was attributed to the electrostatic interactions between the peptide and negatively charged moieties on the cell membrane. PLA-V6K2 NPs showed no toxicity to marrow stromal cells. DOX loaded PLA-V6K2 NPs showed higher toxicity to 4T1 cells and the DNA damage response and apoptosis was delayed compared to the free DOX. DOX or PTX encapsulated in PLA-V6K2 NPs significantly reduced invasion of 4T1 cells compared to those cells treated with the drug in PLA-EG NPs. Invasion of 4T1 cells treated with DOX in PLA-V6K2 and PLA-EG NPs was 5±1% and 30±5%, respectively, and that of PTX was 11±2% and 40±7%. The AUC of DOX in PLA-V6K2 NPs was 67% and 21% higher than those of free DOX and PLA-EG NPs, respectively. DOX loaded PLA-V6K2 NPs injected in C3HeB/FeJ mice inoculated with MTCL syngeneic breast cancer cells displayed higher tumor toxicity than PLA-EG NPs and lower host toxicity than the free DOX. Cationic PLA-V6K2 NPs with higher tumor toxicity than the PLA-EG NPs are potentially useful in chemotherapy.
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