Abstract

In this study a novel pH-responsive magnetic nanocomposite based on reduced graphene oxide was developed for combination of doxorubicin (Dox)-cisplatin (Cis) delivery to destroy the MCF-7 cell line. For this purpose, polyhydroxyethyl methacrylate (PHEMA) was bonded to the reduced graphene oxide through ATRP polymerization using grafting from method. Then the PHEMA hydroxy groups were converted to succinyloxy groups by polyesterification with succinic anhydride. The physicochemical properties of the nanocomposite were investigated via FTIR, SEM, XRD, DLS and TGA analysis. Unique structure of nanocomposite led to simultaneous encapsulation of Dox (75%) and Cis (82%) through ionic interaction, π–π stacking and hydrogen bonding. The obtained nanocomposite was uptake by MCF-7 cells at early first hour because of nanocomposite small size (below 70 nm). Cell viability assay results revealed that the Dox&Cis-loaded nanocomposite showed the highest rate of MCF-7 cells at lowest concentration (IC50 = 0.798 µg/mL) compared to treatment groups received single drug-loaded nanocomposite and free drugs. Dox&Cis-loaded nanocomposite exhibited a synergistic influence with the combination index (CI) value <1. The cell cycle analysis results revealed that the highest amount of apoptosis (cells population in sub G1 was 75%) was observed in the Dox&Cis-loaded nanocomposite treatment group compared with the single drug-loaded nanocomposite and free drugs. Our findings confirmed that combinational therapy by Dox and Cis graphene oxide-based nanocomposite has increased the cytotoxicity in MCF-7 cells by stimulating the apoptotic response.

摘要

在这项研究中，开发了一种基于还原氧化石墨烯的新型 pH 响应磁性纳米复合材料，用于联合阿霉素 (Dox)-顺铂 (Cis) 递送以破坏 MCF-7 细胞系。为此，聚甲基丙烯酸羟乙酯 (PHEMA) 通过 ATRP 聚合使用接枝法与还原的氧化石墨烯键合。然后通过与琥珀酸酐的聚酯化将PHEMA羟基转化为琥珀酰氧基。所述纳米复合材料的物理化学性质进行了研究通过FTIR、SEM、XRD、DLS 和 TGA 分析。纳米复合材料的独特结构通过离子相互作用、π-π 堆积和氢键同时封装了 Dox (75%) 和 Cis (82%)。由于纳米复合材料尺寸小（低于 70 nm），因此获得的纳米复合材料在第一个小时的早期就被 MCF-7 细胞吸收。细胞活力测定结果显示，与接受单一载药纳米复合材料和游离药物的治疗组相比，载有 Dox&Cis 的纳米复合材料在最低浓度 (IC50 = 0.798 µg/mL) 下显示出最高的 MCF-7 细胞率。负载 Dox&Cis 的纳米复合材料表现出协同影响，组合指数 (CI) 值 <1。细胞周期分析结果显示，在 Dox& 顺式负载纳米复合材料治疗组与单一负载纳米复合材料和游离药物的比较。我们的研究结果证实，基于 Dox 和 Cis 氧化石墨烯的纳米复合材料的联合治疗通过刺激细胞凋亡反应增加了 MCF-7 细胞的细胞毒性。