Yu Cui-Yun, Yang Sa, Li Zhi-Ping, Huang Can, Ning Qian, Huang Wen, Yang Wen-Tong, He Dongxiu, Sun Lichun
Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, 421001, China.
Curr Pharm Des. 2016;22(4):506-13. doi: 10.2174/1381612822888151207095620.
The development of slow release nano-sized carriers for efficient antineoplastic drug delivery with a biocompatible and biodegradable pectin-based macromolecular pro-drug for tumor therapy has been reported in this study. Pectin-doxorubicin conjugates (PDC), a macromolecular pro-drug, were prepared via an amide condensation reaction, and a novel amphiphilic core-shell micell based on a PDC macromolecular pro-drug (PDC-M) was self-assembled in situ, with pectin as the hydrophilic shell and doxorubicin (DOX) as the hydrophobic core. Then the chemical structure of the PDC macromolecular pro-drug was identified by both Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance spectroscopy ((1)H-NMR), and proved that doxorubicin combined well with the pectin and formed macromolecular pro-drug. The PDC-M were observed to have an unregularly spherical shape and were uniform in size by scanning electron microscopy (SEM). The average particle size of PDC-M, further measured by a Zetasizer nanoparticle analyzer (Nano ZS, Malvern Instruments), was about 140 nm. The encapsulation efficiency and drug loading were 57.82% ± 3.7% (n = 3) and 23.852% ±2.3% (n = 3), respectively. The in vitro drug release behaviors of the resulting PDC-M were studied in a simulated tumor environment (pH 5.0), blood (pH 7.4) and a lysosome media (pH 6.8), and showed a prolonged slow release profile. Assays for antiproliferative effects and flow cytometry of the resulting PDC-M in HepG2 cell lines demonstrated greater properties of delayed and slow release as compared to free DOX. A cell viability study against endothelial cells further revealed that the resulting PDC-M possesses excellent cell compatibilities and low cytotoxicities in comparison with that of the free DOX. Hemolysis activity was investigated in rabbits, and the results also demonstrated that the PDC-M has greater compatibility in comparison with free DOX. This shows that the resulting PDC-M can ameliorate the hydrophobicity of free DOX. This work proposes a novel strategy for in-situ one-step synthesis of macromolecular pro-drugs and fabrication of a core-shell micelle, demonstrating great potential for cancer chemotherapy.
本研究报道了一种用于高效抗肿瘤药物递送的缓释纳米载体的开发，该载体采用具有生物相容性和可生物降解性的果胶基大分子前药用于肿瘤治疗。通过酰胺缩合反应制备了大分子前药果胶-阿霉素缀合物（PDC），并基于PDC大分子前药原位自组装形成了一种新型两亲性核壳胶束（PDC-M），其中果胶为亲水壳，阿霉素（DOX）为疏水核。然后通过傅里叶变换红外光谱（FTIR）和核磁共振光谱（(1)H-NMR）鉴定了PDC大分子前药的化学结构，证明阿霉素与果胶结合良好并形成了大分子前药。通过扫描电子显微镜（SEM）观察到PDC-M呈不规则球形且尺寸均匀。用Zetasizer纳米颗粒分析仪（Nano ZS，马尔文仪器公司）进一步测量，PDC-M的平均粒径约为140 nm。包封率和载药量分别为57.82%±3.7%（n = 3）和23.852%±2.3%（n = 3）。在模拟肿瘤环境（pH 5.0）、血液（pH 7.4）和溶酶体介质（pH 6.8）中研究了所得PDC-M的体外药物释放行为，结果显示其具有延长的缓释曲线。对所得PDC-M在HepG2细胞系中的抗增殖作用和流式细胞术分析表明，与游离DOX相比，其具有更强的延迟和缓释特性。针对内皮细胞的细胞活力研究进一步表明，与游离DOX相比，所得PDC-M具有优异的细胞相容性和低细胞毒性。在兔子身上研究了溶血活性，结果也表明PDC-M与游离DOX相比具有更高的相容性。这表明所得PDC-M可以改善游离DOX的疏水性。这项工作提出了一种原位一步合成大分子前药和制备核壳胶束的新策略，展示了在癌症化疗中的巨大潜力。
