Abstract:
Co-delivery of anticancer drugs and biologics can provide synergetic effects and outperform single delivery therapies. Here, a nanoparticle (NP) system for co-delivery of methotrexate (MTX) and STAT3 siRNA has been developed and tested in vitro. Mesoporous silica nanoparticles (MSNs) were functionalized with chitosan (ch) by covalent grafting mediated by aminopropyl triethoxysilane (APTES) via glutaraldehyde as the linker. Co-delivery of MTX and STAT3 siRNA to MCF7 cells was demonstrated in cells by flow cytometric analysis and confocal laser scanning fluorescence microscopy for use in breast cancer treatment. MTX either competitively inhibits the dihydrofolate reductase (DHFR) receptor or suppresses the STAT3 metabolic pathway. STAT3 protein plays an essential role in cell division, proliferation and survival. Reduction of the protein by both MTX and STAT3 siRNA, achieved by chMSNs, significantly decreased the viability of breast cancer cells compared to single treatments alone. Cellular uptake of modified NPs was increased over time when additional free MTX was added implicating the DHFR receptor in uptake. In addition, protein corona compositions coated the NPs outer surface, were different between the NPs with and without drug potentially modulating cellular uptake. This study is the first report on co-delivery of MTX and STAT3 siRNA by chitosan modified MSNs.
摘要:
抗癌药物和生物制剂的共同递送可以提供协同作用并且胜过单一递送疗法。这里,已开发并在体外测试了用于甲氨蝶呤(MTX)和STAT3siRNA共递送的纳米颗粒(NP)系统。介孔二氧化硅纳米颗粒(MSN)通过由氨基丙基三乙氧基硅烷(APTES)介导的经由戊二醛作为接头的共价接枝与壳聚糖(ch)官能化。通过流式细胞术分析和用于乳腺癌治疗的共聚焦激光扫描荧光显微镜在细胞中证明了MTX和STAT3siRNA向MCF7细胞的共递送。MTX竞争性抑制二氢叶酸还原酶(DHFR)受体或抑制STAT3代谢途径。STAT3蛋白在细胞分裂中起着至关重要的作用,增殖和生存。通过MTX和STAT3siRNA减少蛋白质,由chMSNs实现,与单一治疗相比,乳腺癌细胞的活力显着降低。当添加额外的游离MTX时,修饰的NP的细胞摄取随时间增加,暗示摄取中的DHFR受体。此外,蛋白质电晕组合物涂覆在NPs的外表面,在有和没有药物可能调节细胞摄取的NP之间是不同的。本研究首次报道了通过壳聚糖修饰的MSNs共同递送MTX和STAT3siRNA。