Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics
Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics
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DOI：
10.1016/j.msec.2019.03.041
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发表时间：
2019-08-01
影响因子：
7.9
通讯作者：
Verma, Rama Shanker
中科院分区：
文献类型：
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作者：
Gupta, Piyush Kumar;Pappuru, Sreenath;Verma, Rama Shanker
最近的研究致力于在药物输送应用中使用生物相容性和可生物降解的无金属完全交替聚酯纳米材料。 【摘要】：以三乙基硼烷(Et3B)/双(三苯基亚正膦)氯化铵(PPNCI)路易斯对作为非金属催化剂,通过近控开环共聚(ROCOP)反应合成了低M-n的市售叔丁基缩水甘油醚(tBGE)与邻苯二甲酸酐(PA)交替共聚物(聚(tBGE-alt-PA)共聚物)。这种生物相容性、血液相容性和可生物降解的共聚物用于制造负载阿霉素 (DOX)、姜黄素 (CUR) 及其组合的不同纳米药物制剂 (NDF)。透射电子显微镜（TEM）成像显示所有平均粒径在 200 至 250 nm 之间的 NDF 均呈球形和核壳内部结构。 X 射线衍射 (XRD) 分析显示 DOX 和 CUR 被包埋到共聚物基质中后均呈现无定形性质。差示扫描比色法 (DSC) 分析显示药物和共聚物之间没有潜在的化学相互作用。细胞药物摄取研究表明，与游离药物相比，所有 NDF 的摄取均有所增加，并且在双药物负载纳米粒子治疗的胰腺癌 (MIA PaCa-2) 细胞中表现出更高的 DOX 和 CUR 积累。体外药物释放动力学研究显示，DOX 和 CUR 在特定的生理环境中具有缓慢持续的药物释放行为以及异常运输。此外，在几种不同的癌细胞系上检查了所有 NDF 的抗肿瘤功效，并在低抑制浓度 (IC50) 值的 MIA PaCa-2 细胞中观察到最大细胞毒性。由于细胞周期停滞在 G2/M 期，这些 NDF 抑制了 MIA PaCa-2 细胞的增殖。结果，MIA PaCa-2 细胞发生凋亡，线粒体膜电位发生显着变化，活性氧 (ROS) 水平增加。未来，这项研究将为此类生物相容性和可生物降解的无金属聚酯在靶向药物输送、组织工程和其他生物医学应用中的使用提供一些新的见解。
Recent research has been directed to the use of biocompatible and biodegradable metal-free fully alternating polyester nanomaterial in drug delivery application. The practice of triethyl borane (Et3B)/Bis(triphenylphosphoranylidene)ammonium chloride (PPNCI) Lewis pair as non-metallic catalyst was carried out to synthesize alternating copolymer of commercially available tert-butyl glycidyl ether (tBGE) and phthalic anhydride (PA) (poly(tBGE-alt-PA) copolymer) of low M-n via nearly controlled ring-opening copolymerization (ROCOP) reaction. This biocompatible, hemocompatible, and biodegradable copolymer was used in the fabrication of different nanodrug formulations (NDFs) loaded with doxorubicin (DOX), curcumin (CUR) and their combination. Transmission electron microscope (TEM) imaging showed the spherical shape and core-shell internal structure for all NDFs with an average particle diameter ranging between 200 and 250 nm. X-ray diffraction (XRD) analysis displayed the amorphous nature of both DOX and CUR after their entrapment into the copolymer matrix. Differential scanning colorimetry (DSC) analysis presented no potential chemical interactions between the drug and copolymer. The cellular drug uptake study showed the increased uptake for all NDFs compared to free drug and exhibited higher DOX and CUR accumulation in dual-drug loaded nanoparticles treated pancreatic cancer (MIA PaCa-2) cells. The in vitro drug release kinetic study displayed the slow sustained drug release behavior with anomalous transport for both DOX and CUR in a defined physiological environment. Further, the anti-tumor efficacy of all NDFs was examined on several different cancer cell lines and maximum cytotoxicity was observed in MIA PaCa-2 cells with low inhibitory concentration (IC50) values. These NDFs inhibited the proliferation of MIA PaCa-2 cells due to cell cycle arrest in G2/M phase. In result, MIA PaCa-2 cells underwent apoptosis with significant changes in mitochondrial membrane potential and increased reactive oxygen species (ROS) level. In future, this study will open several novel insights related to the use of such biocompatible and biodegradable metal-free polyesters in targeted drug delivery, tissue engineering and other biomedical applications.