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通过二丙烯酸化的PTMC-PEG-PTMC三嵌段共聚物的光引发交联制备的可生物吸收水凝胶作为抗肿瘤药物的潜在载体。

Bioresorbable hydrogels prepared by photo-initiated crosslinking of diacrylated PTMC-PEG-PTMC triblock copolymers as potential carrier of antitumor drugs.

作者信息

Wang Yuandou, Xi Laishun, Zhang Baogang, Zhu Qingzhen, Su Feng, Jelonek Katarzyna, Orchel Arkadiusz, Kasperczyk Janusz, Li Suming

机构信息

Institute of High Performance Polymers, Qingdao University of Science and Technology, Qingdao 266042, China.

State Key Laboratory Base of Eco-chemical Engineering, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.

出版信息

Saudi Pharm J. 2020 Mar;28(3):290-299. doi: 10.1016/j.jsps.2020.01.008. Epub 2020 Jan 31.

Abstract

PTMC-PEG-PTMC triblock copolymers were prepared by ring-opening polymerization of trimethylene carbonate (TMC) in the presence of dihydroxylated poly(ethylene glycol) (PEG) with Mn of 6000 and 10,000 as macro-initiator. The copolymers with different PTMC block Lengths and the two PEGs were end functionalized with acryloyl chloride. The resulting diacrylated PEG-PTMC-DA and PEG-DA were characterized by using NMR, GPC and DSC. The degree of substitution of end groups varied from 50.0 to 65.1%. Hydrogels were prepared by photo-crosslinking PEG-PTMC-DA and PEG-DA in aqueous solution using a water soluble photo-initiator under visible light irradiation. The effects of PTMC and PEG block lengths and degree of substitution on the swelling and weight loss of hydrogels were determined. Higher degree of substitution leads to higher crosslinking density, and thus to lower degree of swelling and weight loss. Similarly, higher PTMC block length also leads to lower degree of swelling and weight loss. Freeze dried hydrogels exhibit a highly porous structure with pore sizes from 20 to 100 µm. The biocompatibility of hydrogels was evaluated by MTT assay, hemolysis test, and dynamic clotting time measurements. Results show that the various hydrogels present outstanding cyto- and hemo-compatibility. Doxorubicin was taken as a model drug to evaluate the potential of PEG-PTMC-DA and PEG-DA hydrogels as drug carrier. An initial burst release was observed in all cases, followed by slower release up to more than 90%. The release rate is strongly dependent on the degree of swelling. The higher the degree of swelling, the faster the release rate. Finally, the effect of drug loaded hydrogels on SKBR-3 tumor cells was evaluated in comparison with free drug. Similar cyto-toxicity was obtained for drug loaded hydrogels and free drug at comparable drug concentrations. Therefore, injectable PEG-PTMC-DA hydrogels with outstanding biocompatibility and drug release properties could be most promising as bioresorbable carrier of hydrophilic drugs.

摘要

聚三亚甲基碳酸酯-聚乙二醇-聚三亚甲基碳酸酯(PTMC-PEG-PTMC)三嵌段共聚物是在平均分子量为6000和10000的二羟基化聚乙二醇(PEG)作为大分子引发剂存在的情况下,通过三亚甲基碳酸酯(TMC)的开环聚合反应制备而成。具有不同PTMC嵌段长度的共聚物以及这两种PEG用丙烯酰氯进行了末端官能化。所得的双丙烯酸化PEG-PTMC-DA和PEG-DA通过核磁共振(NMR)、凝胶渗透色谱法(GPC)和差示扫描量热法(DSC)进行了表征。端基的取代度在50.0%至65.1%之间变化。水凝胶是通过在可见光照射下,使用水溶性光引发剂使PEG-PTMC-DA和PEG-DA在水溶液中进行光交联反应制备而成。测定了PTMC和PEG嵌段长度以及取代度对水凝胶溶胀和失重的影响。较高的取代度导致较高的交联密度,从而导致较低的溶胀度和失重。同样,较高的PTMC嵌段长度也导致较低的溶胀度和失重。冻干的水凝胶呈现出高度多孔的结构,孔径在20至100微米之间。通过MTT法、溶血试验和动态凝血时间测量对水凝胶的生物相容性进行了评估。结果表明,各种水凝胶均具有出色的细胞和血液相容性。以阿霉素作为模型药物来评估PEG-PTMC-DA和PEG-DA水凝胶作为药物载体的潜力。在所有情况下均观察到初始的突释,随后是较慢的释放,直至超过90%。释放速率强烈依赖于溶胀度。溶胀度越高,释放速率越快。最后,与游离药物相比,评估了载药的水凝胶对SKBR-3肿瘤细胞的影响。在相当的药物浓度下,载药的水凝胶和游离药物获得了相似的细胞毒性。因此,具有出色生物相容性和药物释放性能的可注射PEG-PTMC-DA水凝胶作为亲水性药物的可生物降解载体可能最具前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a5e7/7078571/ffd32f65b463/gr1.jpg

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