基于还原响应性的生物可降解不饱和聚氨酯的合成及其性能研究
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摘要
设计合成了基于聚富马酸丙二醇酯和二硫键结构的新型不饱和聚氨酯(PPFU-SS);为改善聚氨酯材料的力学性能,引入了聚己内酯(PCL)软段,合成了含有二硫键结构且拉伸性能得到提升的新型不饱和聚氨酯(PPFU-CO-SS);也合成了作为对照的不含二硫键结构的不饱和聚氨酯(PPFU-Lys).示差扫描量热仪(DSC)及热重分析(TGA)测试证明3种材料在150℃以下均具有良好的热稳定性.在外力作用下,3种聚氨酯材料均表现出良好的弹性和较大的形变;引入PCL共聚后的PPFU-CO-SS的拉伸强度得到显著提高,达到了0.8 MPa.降解实验证明,PPFU-SS及PPFU-CO-SS具有显著的还原响应性,在谷胱甘肽存在下降解速度明显加快,与不含谷胱甘肽的对照组相比存在显著性差异. PPFU-CO-SS有更强的疏水性能,其水接触角(93.5°)比PPFU-SS(73.9°)和PPFU-Lys(74.4°)高了约20°.体外细胞培养证明,3种材料均不存在明显的细胞毒性,血管平滑肌细胞在PPFU-SS和PPFU-Lys表面、PPFU-CO-SS表面的增殖速度分别快于或相当于TCPS,说明材料具有优异的细胞相容性.
A novel type of unsaturated polyurethanes(PPFU-SS) containing disulfide bonds was synthesized by using poly(propylene fumarate) as the soft segment and dimethyl L-cystinate dihydrochloride as the chain extender. In order to improve the mechanical properties, polycaprolactone diol(PCL) was copolymerized as the soft segment as well to obtain the novel unsaturated copolymerized polyurethanes(PPFU-CO-SS). Moreover,unsaturated polyurethane(PPFU-Lys) without disulfide bonds was synthesized and used as the control group. The chemical structures of PPFU-SS, PPFU-Lys, and PPFU-CO-SS were characterized by 1 H-NMR, IR, and Raman spectroscopy, revealing that there were many carbon-carbon double bonds and disulfide bonds in PPFU-SS and PPFU-CO-SS. The thermal properties of these three types of PPFU materials were characterized by DSC and TGA, which demonstrated their good thermal stability below 150 °C. The mechanical properties of these PPFUs were analyzed by universal mechanical testing, showing that the tensile strength of PPFU-CO-SS polymer was the highest with a value of 0.8 MPa. Therefore, the copolymerization with PCL has successfully improved the mechanical property of the novel unsaturated polyurethanes. The degradation of reduction-responsive PPFU-SS and PPFU-CO-SS was significantly accelerated in glutathione solution compared with that in phosphate buffered saline, whereas the degradation of PPFU-Lys had no obvious difference in these two types of solutions.Comparatively, PPFU-CO-SS showed a stronger hydrophobicity, water contact angle(93.5°) significantly larger than those of PPFU-SS(73.9°) and PPFU-Lys(74.4°). Culture of smooth muscle cells in vitro demonstrated that none of PPFU-SS, PPFU-Lys, and PPFU-CO-SS had obvious cytotoxicity. The cells cultured on the PPFU-SS and PPFU-Lys surfaces showed faster proliferation rates than those cultured on TCPS, whereas the cell proliferation rate on PPFU-CO-SS was comparable to that on TCPS. In conclusion, these results demonstrated that the reduction-responsive polyurethanes possess good mechanical strength, thermal stability, degradability in response to reductants, low cytotoxicity, and cell coMPatibility, and thus hold great potential in fields of drug delivery,tissue engineering, regenerative medicine, and therapy of diseases. Furthermore, the unsaturated and high active carbon-carbon double bonds can be used to graft desired molecules, enabling the diverse functionalization and thereby applications.
A novel type of unsaturated polyurethanes(PPFU-SS) containing disulfide bonds was synthesized by using poly(propylene fumarate) as the soft segment and dimethyl L-cystinate dihydrochloride as the chain extender. In order to improve the mechanical properties, polycaprolactone diol(PCL) was copolymerized as the soft segment as well to obtain the novel unsaturated copolymerized polyurethanes(PPFU-CO-SS). Moreover,unsaturated polyurethane(PPFU-Lys) without disulfide bonds was synthesized and used as the control group. The chemical structures of PPFU-SS, PPFU-Lys, and PPFU-CO-SS were characterized by 1 H-NMR, IR, and Raman spectroscopy, revealing that there were many carbon-carbon double bonds and disulfide bonds in PPFU-SS and PPFU-CO-SS. The thermal properties of these three types of PPFU materials were characterized by DSC and TGA, which demonstrated their good thermal stability below 150 °C. The mechanical properties of these PPFUs were analyzed by universal mechanical testing, showing that the tensile strength of PPFU-CO-SS polymer was the highest with a value of 0.8 MPa. Therefore, the copolymerization with PCL has successfully improved the mechanical property of the novel unsaturated polyurethanes. The degradation of reduction-responsive PPFU-SS and PPFU-CO-SS was significantly accelerated in glutathione solution compared with that in phosphate buffered saline, whereas the degradation of PPFU-Lys had no obvious difference in these two types of solutions.Comparatively, PPFU-CO-SS showed a stronger hydrophobicity, water contact angle(93.5°) significantly larger than those of PPFU-SS(73.9°) and PPFU-Lys(74.4°). Culture of smooth muscle cells in vitro demonstrated that none of PPFU-SS, PPFU-Lys, and PPFU-CO-SS had obvious cytotoxicity. The cells cultured on the PPFU-SS and PPFU-Lys surfaces showed faster proliferation rates than those cultured on TCPS, whereas the cell proliferation rate on PPFU-CO-SS was comparable to that on TCPS. In conclusion, these results demonstrated that the reduction-responsive polyurethanes possess good mechanical strength, thermal stability, degradability in response to reductants, low cytotoxicity, and cell coMPatibility, and thus hold great potential in fields of drug delivery,tissue engineering, regenerative medicine, and therapy of diseases. Furthermore, the unsaturated and high active carbon-carbon double bonds can be used to graft desired molecules, enabling the diverse functionalization and thereby applications.
引文
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11 Ratner B D,Hoffman A S,Schoen F J,Lemons J E.MRS Bull,2006,31(1):58-60
12 Fu Hao(傅皓),Li Sai(李赛),Li Jiehua(李洁华),Xie Xingyi(谢兴益).J Biomed Eng(生物医学工程学杂志),2003,20(2):348-351
13 Lelah M D,Cooper S L.Polyurethane in Medicine.Boca Raton:CRC Press,Inc.,1986.225
14 Feng Xuepeng(冯学鹏),Jian Peng(简鹏),Ding lin(丁琳),Fei Junhao(费俊豪),Sheng Yang(盛扬),Zhang Rong(张嵘).Acta Polymerica Sinica(高分子学报),2016,(8):1062-1071
15 Boretos J W,Pierce W S.Science,1967,158(3807):1481-1482
16 Kasper F K,Tanahashi K,Fisher J P,Mikos A G.Nat Protoc,2009,4(4):518
17 Zheng L,Wang Z,Li C,Xiao Y,Zhang D,Guan G,Zhu W.Polymer,2013,54(2):631-638
18 Nair D P,Podgorski M,Chatani S,Gong T,Xi W,Fenoli C R,Bowman C N.Chem Mat,2013,26(1):724-744
19 Hoyle C E,Lowe A B,Bowman C N.Chem Soc Rev,2010,39(4):1355-1387
20 Wu G,Fang Y-Z,Yang S,Lupton J R,Turner N D.J Nutr,2004,134(3):489-492
21 Borok Z,Buhl R,Hubbard R C,Holroyd K J,Roum J H,Czerski D B,Crystal R G,Grimes G J,Bokser A D,Cantin A M.Lancet,1991,338(8761):215-216
22 Saito G,Swanson J A,Lee K D.Adv Drug Deliv Rev,2003,55(2):199-215
23 Lomaestro B M,Malone M.Ann Pharmacother,1995,29(12):1263
24 Arjinpathana N,Asawanonda P.J Dermatol Treat,2012,23(2):97-102
25 Bardellini E,Bindi P,Borzone S,Caglieris S,Dagnino F,Testa R.Adv Ther,1992,9(2):116-122
26 Hu B,Ye C,Gao C.J Appl Polym Sci,2015,132(24):42065
27 Wygant J C,Prill E J,Carter D E,Kucia R R.US patent,C07C67/58,3360546.1963-09-16
28 Hu B,Deng J,Zheng H,Yu S,Gao C.Macromol Rapid Commun,2016,37(16):1331-1336
29 van Wart H E,Lewis A,Scheraga H A,Saeva F D.Proc Natl Acad Sci USA,1973,70(9):2619
30 Averous L,Moro L,Dole P,Fringant C.Polymer,2000,41(11):4157-4167
31 Pan Zuren(潘祖仁).Polymer Chemistry(高分子化学).Beijing(北京):Chemical Industry Press(化学工业出版社),2007.252-254
32 Arima Y,Iwata H.Biomaterials,2007,28(20):3074-3082
33 Faucheux N,Schweiss R,Lützow K,Werner C,Groth T.Biomaterials,2004,25(14):2721-2730
34 Zhu Y,Gao C,Shen J.Biomaterials,2002,23(24):4889-4895
2 Liu Xinyu(刘欣宇),Hu Jin(胡瑾),Guo Jianwen(郭建文),Wang Guilin(王贵林),Gao Weiping(高卫平).ActaPolymerica Sinica(高分子学报),2018,(1):90-98
3 Liu R,Zhang Y,Zhao X,Agarwal A,Mueller L J,Feng P.J Am Chem Soc,2010,132(5):1500-1501
4 Overall C M,Kleifeld O.Nat Rev Cancer,2006,6(3):227-239
5 Guo Heze(郭和泽),Song Sheng(宋晟),Dai Tingting(戴婷婷),Li Shengli(李圣利),Dou Hongjing(窦红静).ActaPolymerica Sinica(高分子学报),2018,(8):1127-1140
6 Napoli A,Valentini M,Tirelli N,Müller M,Hubbell J A.Nat Mater,2004,3(3):183-189
7 Meng F,Hennink W E,Zhong Z.Biomaterials,2009,30(12):2180-2198
8 Lu Y,Aimetti A A,Langer R,Gu Z.Nat Rev Mater,2016,2(1):16075
9 Jeong B,Gutowska A.Trends Biotechnol,2002,20(8):360-360
10 Hoffman A S,Stayton P S,Bulmus V,Chen G,Chen J,Cheung C,Chilkoti A,Ding Z,Dong L,Fong R,Lackey C A,Long C J,Miura M,Morris J E,Murthy N,Nabeshima Y,Park T G,Press O W,Shimoboji T,Shoemaker S,Yang H J,Monji N,Nowinski R C,Cole C A,Priest J H,Harris J M,Nakamae K,Nishino T,Miyata T.J Biomed Mater Res,2000,52(4):577-586
11 Ratner B D,Hoffman A S,Schoen F J,Lemons J E.MRS Bull,2006,31(1):58-60
12 Fu Hao(傅皓),Li Sai(李赛),Li Jiehua(李洁华),Xie Xingyi(谢兴益).J Biomed Eng(生物医学工程学杂志),2003,20(2):348-351
13 Lelah M D,Cooper S L.Polyurethane in Medicine.Boca Raton:CRC Press,Inc.,1986.225
14 Feng Xuepeng(冯学鹏),Jian Peng(简鹏),Ding lin(丁琳),Fei Junhao(费俊豪),Sheng Yang(盛扬),Zhang Rong(张嵘).Acta Polymerica Sinica(高分子学报),2016,(8):1062-1071
15 Boretos J W,Pierce W S.Science,1967,158(3807):1481-1482
16 Kasper F K,Tanahashi K,Fisher J P,Mikos A G.Nat Protoc,2009,4(4):518
17 Zheng L,Wang Z,Li C,Xiao Y,Zhang D,Guan G,Zhu W.Polymer,2013,54(2):631-638
18 Nair D P,Podgorski M,Chatani S,Gong T,Xi W,Fenoli C R,Bowman C N.Chem Mat,2013,26(1):724-744
19 Hoyle C E,Lowe A B,Bowman C N.Chem Soc Rev,2010,39(4):1355-1387
20 Wu G,Fang Y-Z,Yang S,Lupton J R,Turner N D.J Nutr,2004,134(3):489-492
21 Borok Z,Buhl R,Hubbard R C,Holroyd K J,Roum J H,Czerski D B,Crystal R G,Grimes G J,Bokser A D,Cantin A M.Lancet,1991,338(8761):215-216
22 Saito G,Swanson J A,Lee K D.Adv Drug Deliv Rev,2003,55(2):199-215
23 Lomaestro B M,Malone M.Ann Pharmacother,1995,29(12):1263
24 Arjinpathana N,Asawanonda P.J Dermatol Treat,2012,23(2):97-102
25 Bardellini E,Bindi P,Borzone S,Caglieris S,Dagnino F,Testa R.Adv Ther,1992,9(2):116-122
26 Hu B,Ye C,Gao C.J Appl Polym Sci,2015,132(24):42065
27 Wygant J C,Prill E J,Carter D E,Kucia R R.US patent,C07C67/58,3360546.1963-09-16
28 Hu B,Deng J,Zheng H,Yu S,Gao C.Macromol Rapid Commun,2016,37(16):1331-1336
29 van Wart H E,Lewis A,Scheraga H A,Saeva F D.Proc Natl Acad Sci USA,1973,70(9):2619
30 Averous L,Moro L,Dole P,Fringant C.Polymer,2000,41(11):4157-4167
31 Pan Zuren(潘祖仁).Polymer Chemistry(高分子化学).Beijing(北京):Chemical Industry Press(化学工业出版社),2007.252-254
32 Arima Y,Iwata H.Biomaterials,2007,28(20):3074-3082
33 Faucheux N,Schweiss R,Lützow K,Werner C,Groth T.Biomaterials,2004,25(14):2721-2730
34 Zhu Y,Gao C,Shen J.Biomaterials,2002,23(24):4889-4895