Synergistically Enhanced Inhibitory Effects of Pullulan Nanoparticle-Mediated Co-Delivery of Lovastatin and Doxorubicin to Triple-Negative Breast Cancer Cells
Synergistically Enhanced Inhibitory Effects of Pullulan Nanoparticle-Mediated Co-Delivery of Lovastatin and Doxorubicin to Triple-Negative Breast Cancer Cells
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普鲁兰纳米颗粒介导的洛伐他汀和多柔比星对三阴性乳腺癌细胞的协同增强抑制作用
DOI：
10.1186/s11671-019-3146-0
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发表时间：
2019-09-13
影响因子：
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通讯作者：
Deng, Xiyun
中科院分区：
文献类型：
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作者：
Wu, Di;Chen, Yao;Deng, Xiyun
三阴性乳腺癌（TNBC）是一种易产生耐药性且治疗困难的乳腺癌亚型。本研究将水溶性普鲁兰多糖（pullulan）与洛伐他汀（lovastatin，LV）接枝，制备了一种新型两亲性共轭物-普鲁兰多糖包裹的LV（PLV）。以普鲁兰多糖与LV的三种不同比例合成PLV偶联物，并用傅立叶变换红外光谱（FTIR）对其进行表征。通过质子NMR分析，LV的取代度（DS）以摩尔比表示，PLV（1/2）、PLV（1/3）和PLV（1/4）分别为7.87%、3.58%和3.06%。我们选择PLV（1/2）结合物来制备负载阿霉素（DXR）的PLV纳米粒（PLV/DXR NPs），因为其上级性质。通过动态光散射测定，PLV（1/2）NPs的平均尺寸和zeta电位分别为177.6 nm和− 11.66 mV，PLV/DXR NPs的平均尺寸和zeta电位分别为225.6 nm和− 10.51 mV。体外药物释放曲线显示PLV/DXR NPs在72 h内持续释放DXR，在pH 5.4（97.90%）比pH 7.4（76.15%）更稳定。在细胞毒性研究中，PLV/DXR NP对TNBC MDA-MB-231细胞增殖的抑制作用大于非TNBC MDA-MB-453细胞（IC500.60 vs 11.05 μM）。制备负载FITC的PLV/DXR NP以研究细胞摄取：两种细胞系均显示NP的时间依赖性摄取，但进入MDA-MB-231细胞的NP数量大于进入MDA-MB-453细胞的NP数量。LV和DXR的基于普鲁兰多糖的NP共递送可以有效地抑制TNBC细胞，这可能有助于设计用于治疗TNBC的强大药物递送系统。
Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is prone to drug resistance and difficult to treat. In this study, we grafted water-soluble pullulan with lovastatin (LV) to develop a novel amphiphilic conjugate, pullulan-encapsulated LV (PLV). The PLV conjugate was synthesized with three different ratios of pullulan to LV and characterized by Fourier transform infrared (FTIR). The degree of substitution (DS) of LV in terms of molar ratio was 7.87%, 3.58%, and 3.06% for PLV (1/2), PLV (1/3), and PLV (1/4), respectively, by proton NMR analysis. We selected the PLV (1/2) conjugate to prepare doxorubicin (DXR)-loaded PLV nanoparticles (PLV/DXR NPs) because of its superior properties. The average size and zeta potential for PLV (1/2) NPs were 177.6 nm and − 11.66 mV, respectively, determined by dynamic light scattering, and those for PLV/DXR NPs were 225.6 nm and − 10.51 mV, respectively. In vitro drug release profiling showed that PLV/DXR NPs sustainably released DXR within 72 h, which was more robust at pH 5.4 (97.90%) than pH 7.4 (76.15%). In the cytotoxicity study, PLV/DXR NPs showed greater inhibition of proliferation of TNBC MDA-MB-231 than non-TNBC MDA-MB-453 cells (IC500.60 vs 11.05 μM). FITC-loaded PLV/DXR NPs were prepared to investigate cellular uptake: both cell lines showed a time-dependent uptake of NPs, but the number of NPs entering MDA-MB-231 cells was greater than that entering the MDA-MB-453 cells. Pullulan-based NP co-delivery of LV and DXR could efficiently inhibit TNBC cells, which may help in designing a powerful drug delivery system for treating TNBC.