非线形聚合物构筑光响应胶束用于药物控制释放的研究
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摘要
由于在药物增溶和延长体内循环时间上具有显著优势,两亲性聚合物自组装胶束在药物传输领域吸引了越来越多的关注。进一步通过分子设计赋予胶束刺激响应性,有望实现对载体释药行为的控制。本研究利用非线形聚合物较多的末端官能团与光响应分子的亲疏水转换反应,合成了具有光响应能力的两亲性非线形聚合物,构筑了两种具备良好生物相容性的光响应聚合物胶束,探索了将其作为智能载体用于药物控制释放的可能性。具体开展了以下两个工作：
1、利用具备良好生物相容性和隐身特性的梳状聚乙二醇(CPEG)的末端羟基,将可在光照下发生沃尔夫重排反应的重氮萘醌(DNQ)分子引入到其结构中,成功合成了光响应的两亲性梳状聚乙二醇衍生物CPEG-g-DNQ。这种两亲性的梳状聚合物可以在水中自发地组装成尺寸约为135nm的球形胶束,以尼罗红为荧光探针测得其临界胶束浓度为0.064mg mL-1.体外细胞毒性测试表明这种胶束具有良好的生物相容性。由于聚合物结构中的疏水重氮萘醌在光照下会转变成亲水的3-茚酸,胶束经紫外光照射后发生解体。荧光染料香豆素102被选作疏水模型药物载入胶束内核,荧光发射光谱结果表明,光照可以调控香豆素102的释放行为。由于重氮萘醌在近红外光下也能发生沃尔夫重排,这种具备良好生物相容性的胶束在药物传输领域具有诱人的应用前景。
2、将在不同光照下能发生可逆亲疏水转变的螺吡喃分子与具备良好生物相容性和生物可降解能力的超支化聚磷酸酯相结合,设计合成了一种螺吡喃改性的超支化聚磷酸酯(HPHEEP-SP)。透射电子显微镜和动态光散射测试结果显示,这种两亲性聚合物在水中自组装成尺寸约为186nm的球形胶束,荧光探针法测得该聚合物的临界胶束浓度为0.052mg mL-1。MTT测试结果表明,所得胶束的细胞毒性较低。利用螺吡喃在不同光照下的光致异构转变,实现了对胶束粒径在紫外光和可见光交替照射下的可逆调控。这种胶束可以成功包载抗癌药物阿霉素,载药量和包封率分别为8.98%和49.33%。体外药物释放实验表明,胶束对抗癌药物具有缓释能力。最后,我们还让胶束成功包载了模型药物香豆素102,荧光发射光谱结果表明,光照可以调控胶束对模型药物的包载、释放与再包载过程。这种具备良好生物相容性和生物可降解能力的可逆光响应胶束在药物的控制释放领域具有潜在的应用价值。
Polymeric micelles self-assembled from amphiphilic polymers have attracted more and more attention in the field of drug delivery due to their distinct advantages including improved solubility of hydrophobic anticancer drugs and prolonged circulation time. Additionally, controlled drug release can be achieved by molecular design to prepare stimuli-responsive micelles. In this study, amphiphilic non-linear polymers were synthesized by introducing hydrophobic photo-responsive groups into the structures of hydrophilic non-linear polymers. Photo-responsive micelles with excellent biocompatibility were then constructed by solution self-assembly. Model drug was at last encapsulated into the micelles to explore the possibility of the micelles as smart drug carriers for controlled drug release. The detailed two works are as follows:
Biocompatible Micelles Based on Comb-Like PEG Derivates:Formation, Characterization and Photo-Responsiveness
A novel comb-like derivative CPEG-g-DNQ was prepared by incorporating light responsive2-diazo-1,2-naphthoquinone (DNQ) groups into the structure of comb-like poly(ethylene glycol)(CPEG). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results showed that CPEG-g-DNQ self-assembled into spherical micelles with an average size of about135nm in water. The critical micelle concentration (CMC) of the micelles was determined as0.064mg mL-1by fluorescence spectroscopy using Nile Red as a fluorescence probe. MTT assay revealed that the micelles are biocompatible. Upon exposure to light, the micelles could be disrupted because of the conversion of hydrophobic DNQ to hydrophilic3-indenecarboylic acid. Additionally, hydrophobic coumarin102was successfully loaded into the micelles and photo-induced ON-OFF release was demonstrated by fluorescence spectroscopy. These photo-responsive micelles might have great potential for controlled release of hydrophobic drugs.
Biocompatible and reversibly photo-responsive micelles constructed from spiropyran-modified hyperbranched polyphosphates for smart drug delivery Biocompatible and reversibly photo-responsive micelles were constructed from an amphiphilic spiropyran-containing hyperbranched polyphosphate (HPHEEP-SP) and applied for controlled release and re-encapsulation of drugs. HPHEEP-SP was designed and synthesized by modification of hydrophilic hyperbranched polyphosphate (HPHEEP-OH) with hydrophobic, light-responsive spiropyran (SP) molecules. DLS and TEM measurements revealed that the polymer can self-assemble into spherical micelles with an average diameter of186nm in aqueous solution. The critical micelle concentration (CMC) of the micelles was0.052mg ml-1determined by fluorescence spectroscopy using Nile Red as a fluorescence probe. Cell viability tests against two types of cells indicated that the micelles have excellent biocompatibility. By illuminating the micelles with365nm UV light, the diameter of the micelles decreased gradually to about100nm because of the transformation of hydrophobic spiropyran to hydrophilic merocyanine. Followed irradiating the micelles with620nm visible light, the diameter of the micelles was restored. Anticancer drug doxorubicin was successfully loaded into the micelles with loading content of8.98%and loading efficiency of49.33%. In vitro release experiments revealed that the drug-loaded micelles showed significant sustained release behavior. At last, model drug coumarin102was also encapsulated into the micelles. Then, controlled release under365nm UV light and re-encapsulation under620nm visible light were demonstrated by fluorescence spectroscopy. These photo-responsive and biocompatible polymeric micelles self-assembled from spiropyran-modified hyperbranched polyphosphates might have great potential as smart carriers in the field of drug delivery.
1、利用具备良好生物相容性和隐身特性的梳状聚乙二醇(CPEG)的末端羟基,将可在光照下发生沃尔夫重排反应的重氮萘醌(DNQ)分子引入到其结构中,成功合成了光响应的两亲性梳状聚乙二醇衍生物CPEG-g-DNQ。这种两亲性的梳状聚合物可以在水中自发地组装成尺寸约为135nm的球形胶束,以尼罗红为荧光探针测得其临界胶束浓度为0.064mg mL-1.体外细胞毒性测试表明这种胶束具有良好的生物相容性。由于聚合物结构中的疏水重氮萘醌在光照下会转变成亲水的3-茚酸,胶束经紫外光照射后发生解体。荧光染料香豆素102被选作疏水模型药物载入胶束内核,荧光发射光谱结果表明,光照可以调控香豆素102的释放行为。由于重氮萘醌在近红外光下也能发生沃尔夫重排,这种具备良好生物相容性的胶束在药物传输领域具有诱人的应用前景。
2、将在不同光照下能发生可逆亲疏水转变的螺吡喃分子与具备良好生物相容性和生物可降解能力的超支化聚磷酸酯相结合,设计合成了一种螺吡喃改性的超支化聚磷酸酯(HPHEEP-SP)。透射电子显微镜和动态光散射测试结果显示,这种两亲性聚合物在水中自组装成尺寸约为186nm的球形胶束,荧光探针法测得该聚合物的临界胶束浓度为0.052mg mL-1。MTT测试结果表明,所得胶束的细胞毒性较低。利用螺吡喃在不同光照下的光致异构转变,实现了对胶束粒径在紫外光和可见光交替照射下的可逆调控。这种胶束可以成功包载抗癌药物阿霉素,载药量和包封率分别为8.98%和49.33%。体外药物释放实验表明,胶束对抗癌药物具有缓释能力。最后,我们还让胶束成功包载了模型药物香豆素102,荧光发射光谱结果表明,光照可以调控胶束对模型药物的包载、释放与再包载过程。这种具备良好生物相容性和生物可降解能力的可逆光响应胶束在药物的控制释放领域具有潜在的应用价值。
Polymeric micelles self-assembled from amphiphilic polymers have attracted more and more attention in the field of drug delivery due to their distinct advantages including improved solubility of hydrophobic anticancer drugs and prolonged circulation time. Additionally, controlled drug release can be achieved by molecular design to prepare stimuli-responsive micelles. In this study, amphiphilic non-linear polymers were synthesized by introducing hydrophobic photo-responsive groups into the structures of hydrophilic non-linear polymers. Photo-responsive micelles with excellent biocompatibility were then constructed by solution self-assembly. Model drug was at last encapsulated into the micelles to explore the possibility of the micelles as smart drug carriers for controlled drug release. The detailed two works are as follows:
Biocompatible Micelles Based on Comb-Like PEG Derivates:Formation, Characterization and Photo-Responsiveness
A novel comb-like derivative CPEG-g-DNQ was prepared by incorporating light responsive2-diazo-1,2-naphthoquinone (DNQ) groups into the structure of comb-like poly(ethylene glycol)(CPEG). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results showed that CPEG-g-DNQ self-assembled into spherical micelles with an average size of about135nm in water. The critical micelle concentration (CMC) of the micelles was determined as0.064mg mL-1by fluorescence spectroscopy using Nile Red as a fluorescence probe. MTT assay revealed that the micelles are biocompatible. Upon exposure to light, the micelles could be disrupted because of the conversion of hydrophobic DNQ to hydrophilic3-indenecarboylic acid. Additionally, hydrophobic coumarin102was successfully loaded into the micelles and photo-induced ON-OFF release was demonstrated by fluorescence spectroscopy. These photo-responsive micelles might have great potential for controlled release of hydrophobic drugs.
Biocompatible and reversibly photo-responsive micelles constructed from spiropyran-modified hyperbranched polyphosphates for smart drug delivery Biocompatible and reversibly photo-responsive micelles were constructed from an amphiphilic spiropyran-containing hyperbranched polyphosphate (HPHEEP-SP) and applied for controlled release and re-encapsulation of drugs. HPHEEP-SP was designed and synthesized by modification of hydrophilic hyperbranched polyphosphate (HPHEEP-OH) with hydrophobic, light-responsive spiropyran (SP) molecules. DLS and TEM measurements revealed that the polymer can self-assemble into spherical micelles with an average diameter of186nm in aqueous solution. The critical micelle concentration (CMC) of the micelles was0.052mg ml-1determined by fluorescence spectroscopy using Nile Red as a fluorescence probe. Cell viability tests against two types of cells indicated that the micelles have excellent biocompatibility. By illuminating the micelles with365nm UV light, the diameter of the micelles decreased gradually to about100nm because of the transformation of hydrophobic spiropyran to hydrophilic merocyanine. Followed irradiating the micelles with620nm visible light, the diameter of the micelles was restored. Anticancer drug doxorubicin was successfully loaded into the micelles with loading content of8.98%and loading efficiency of49.33%. In vitro release experiments revealed that the drug-loaded micelles showed significant sustained release behavior. At last, model drug coumarin102was also encapsulated into the micelles. Then, controlled release under365nm UV light and re-encapsulation under620nm visible light were demonstrated by fluorescence spectroscopy. These photo-responsive and biocompatible polymeric micelles self-assembled from spiropyran-modified hyperbranched polyphosphates might have great potential as smart carriers in the field of drug delivery.
引文
[1]Allen T. M., Cullis P. R., Science,2004,303,1818.
[2]Soussan E., Cassel S., Blanzat M., et al.,Angew. Chem. Int. Ed.,2009,48,274.
[3]Rijcken C. J. F., Soga O., Hennink W. E., et al.,J. Control. Release,2007,120,131.
[4]Lian T., Ho R. J. Y., J. Pharm. Sci.,2001,90,667.
[5]Gaucher G., Dufresne M. H., Sant V. P., et al., J. Control. Release,2005,109,69.
[6]Adams M. L., Lavasanifar A., Kwon G. S.,J. Pharm. Sci.,2003,92,1343.
[7]Discher D. E., Eisenberg A., Science,2002,297,967.
[8]Discher B. M., Won Y. Y., Ege D. S., et al., Science,1999,284,1143.
[9]Discher D. E., Ortiz V., Srinivas G., et al., Prog. Polym. Sci.,2007,32,838.
[10]Ramanan R. M. K., Chellamuthu P., Tang L. P., et al., Biotechnol. Prog.,2006,22,118.
[11]Wang J. J., Sung K. C., Hu O. Y. P., et al.,J. Control. Release,2006,115,140.
[12]Uekama K., Hirayama F., Irie T., Chem. Rev.,1998,98,2045.
[13]Bianco A., Kostarelos K., Prato M., Curr. Opin. Chem. Biol,2005,9,674.
[14]Gillies E. R., Frechet J. M. J., Drug Discovery Today,2005,10,35.
[15]Kwon G. S., Okano J.,Adv. Drug Delivery Rev.,1996,21,107.
[16]Rosier A., Vandermeulen G. W. M., Klok H. A., Adv. Drug Delivery Rev.,2001,53,95.
[17]Kataoka K., Harada A., Nagasaki Y., Adv. Drug Delivery Rev.,2001,47,113.
[18]Torchilin V. P., Cell. Mol Life Sci.,2004,61,2549.
[19]Gaucher G., Satturwar P., Jones M. C., et al., Eur. J. Pharm. Biopharm.,2010,76,147.
[20]Oerlemans C., Bult W., Bos M., et al, Pharm. Res.,2010,27,2569.
[21]Kedar U., Phutane P., Shidhaye S., et al,Nanomedicine:NBM,2010,6,714.
[22]Nishiyama N., Kataoka K., Pharmacol. Therap.,2006,112,630.
[23]Motornov M., Roiter Y., Tokarev I., et al, Prog. Polym. Sci.,2010,35,174.
[24]Jain S., Bates F. S., Science,2003,300,460.
[25]Sun J., Shi Q., Chen X. S., et al, Macromol Chem. Phys.,2008,209,1129.
[26]Zhang L. F., Eisenberg A., Polym. Adv. Technol,1998,9,677.
[27]Yu K., Eisenberg A., Macromolecules,1998,3,3509.
[28]Pochan D. J., Chen Z. Y.. Cui H. G., el al. Science,2004,306.94.
[29]Guo Z. P., Li Y. H., Tian H. Y.. et al, Langmuir,2009,25,9690.
[30]Soo P. L., Eisenberg A.,J. Polym. Sci., Part B:Polym. Phys.,2004,42,923.
[31]Blanazs A., Armes S. P., Ryan A. J., Macromol. Rapid Commun.,2009.30.267.
[32]Rodriguez-Hernandez J., Checot F., Gnanou Y., et al, Prog. Polym. Sci.,2005,30,691.
[33]Lonsdale D. E., Whittaker M. R., Monteiro M. J., J. Polym. Sci.:Parr A:Polym. Chem., 2009.47,6292.
[34]Francisa M. F., Pireddaa M., Winnika F. M., J. Controlled Release,2003,93,59.
[35]Brown M. D., Schatzlein A., Brownlie A., et al., Bioconjugate Chem.,2000,11,880.
[36]Cheng W. P., Gray A. I., Tetley L., et al, Biomacromolecules,2006,7,1509.
[37]Li C., Ge Z., Fang J., et al, Macromolecules,2009,42,2916.
[38]Thompson C. J., Ding C. X., Qu X. Z., et al, Colloid Polym. Sci.,2008,286,1511.
[39]Wang B. B., Zhang X., Jia X. R., et al., J. Polym. Sci.:Part A:Polym. Chem.,2005,43, 5512.
[40]Schenning A. P. H. J., Elissen-Roman C., Weener J. W., et al, J. Am. Chem. Soc.,1998, 120,8199.
[41]Cho B. K., Jain A., Nieberle J., et al, Macromolecules,2004,37,4227.
[42]Kim K. T., Winnik. M. A., Manners I., Soft Matter,2006,2,957.
[43]Gao C.. Yan D., Prog. Polym. Sci.,2004,29,183.
[44]Yan D., Zhou Y., Hou J., Science,2004,303,65.
[45]Zhou Y., Yan D., Angew. Chem. Int. Ed,2004,43,4896.
[46]Zhou Y., Yan D., Angew. Chem. Int. Ed,2005,44,3223.
[47]Zhou Y., Yan D., J. Am. Chem. Soc.,2005,127,10468.
[48]Zhou Y., Yan D., Chem. Commun.,2009,1172.
[49]Zhou Y., Huang W., Liu J., et al,Adv. Mater,2010,22,4567.
[50]del Barrio J., Oriol L., Sanchez C., et al., J. Am. Chem. Soc.,2010,132,3762.
[51]Khanna K., Varshney S., Kakkar A., Polym. Chem.,2010,1,1171.
[52]Gillies E. R., Frechet J. M. J., Bioconjugate Chem.,2005.16,361.
[53]Wang C. H., Wang C. H., Hsiue G. H., J. Control. Release,2005,108,140.
[54]Yao J., Ruan Y., Zhai T., et al. Polymer,2011,52,3396.
[55]Sun H., Guo B., Li X., et al., Biomacromolecules,2010,11,848
[56]Wang D., Yin J., Zhu Z. Y., et al., Macromolecules,2006,39,7378.
[57]Roy D., Cambre J. N., Sumerlin B. S., Chem. Commun.,2008,2477.
[58]Cheng C., Wei H., Shi B. X., et al., Biomaterials,2008,29,497.
[59]Nakayama M.; Okano T., Biomacromolecules,2005,6,2320
[60]Akimoto J., Nakayama M., Sakai K., et al, Biomacromolecules,2009,10,1331.
[61]Wang J., Pelletier M., Zhang H., et al, Langmuir,2009,25,13201.
[62]Kotharangannagari V. K., Sanchez-Ferrer A., Ruokolainen J., Macromolecules,2011,44, 4569.
[63]Yan Q., Hu J., Zhou R., et al., Chem. Commun.,2012,48,1913.
[64]Schumers J. M., Fustin C. A., Gohy J. F., Macromol Rapid Commun.,2010,31,1588.
[65]Zhao Y., J. Mater. Chem.,2009,19,4887.
[66]Schmaljohann D.,Adv. Drug. Delivery Rev,2006,58,1655.
[67]Grabe M., Oster G., J. Gen. Physiol,2001,117,329.
[68]Watson P., Jones A. T., Stephens D. J.,Adv. Drug Delivery Rev.,2005,57,43.
[69]Martin T. J., Prochazka K., Munk P., et al., Macromolecules,1996,29,6071.
[70]Liu S., Armes S. P., Angew. Chem. Int. Ed.,2002,41,1413.
[71]Liu S., Weaver J. V. M., Save M., et al., Langmuir,2002,18,8350.
[72]Liu S., Weaver J. V. M., Tang Y., et al., Macromolecules,2002,35,6121.
[73]Fujii S., Cai Y., Weaver J. V. M., et al.,J. Am. Chem. Soc.,2005,127,7304.
[74]Sumerlin B. S., Lowe A. B., Thomas D. B., et al., Macromolecules,2003,36,5982.
[75]Xu X., Smith A. E., Kirkland S. E., et al., Macromolecules,2008,41,8429.
[76]Bae Y., Fukushima S., Harada A., et al., Angew. Chem. Int. Ed.,2003,42,4640.
[77]Chen W., Meng F., Li F., et al, Biomacromolecules,2009,10,1727.
[78]Li Y., Lokitz B. S., McCormick C. L., Angew. Chem. Int. Ed.,2006,45,5792.
[79]Wei H., Cheng S. X., Zhang X. Z., et al.,Prog. Polym. Sci.,2009,34,893.
[80]Cui Q., Wu F., Wang E., J. Phys. Chem. B,2011,115,5913.
[81]Jochum F. D., Roth P. J., Kessler D., et al., Biomacromolecules,2010,11,2432.
[82]Feil H., Bae Y. H., Feijen J., et al., Macromolecules,1993,26,2496.
[83]Shibayama M., Mizutani S., Nomura S., Macromolecules,1996,29,2019.
[84]Cammas S., Suzuki K., Sone C., et al., J. Control. Release,1997,48,157
[85]Chung J. E., Yokoyama M., Yamato M., et al.,J. Control. Release,1999.62.115.
[86]Chung J. E., Yokoyama M., Okano T., J. Control. Release,2000,65,93.
[87]Nakayama M., Okano T., Miyazaki T., et al.,J. Control. Release,2006,115,46.
[88]Wei H., Zhang X. Z., Zhou Y., et al., Biomaterials,2006,27,2028.
[89]Wei H., Zhang X. Z., Cheng H., et al., J. Control. Release,2006,116,266.
[90]Chang C., Wei H., Feng J., et al., Macromolecul.es,2009,42,4838.
[91]Napoli A., Valentini M., Tirelli N., et al., Nat. Mater.,2004,3,183.
[92]Napoli A., Boerakker M. J., Tirelli N., et al., Langmuir,2004,20,3487.
[93]Ma N., Li Y., Ren H., et al., Polym. Chem.,2010,1,1609.
[94]Kakizawa Y., Harada A., Kataoka K., J. Am. Chem. Soc.,1999,121,11247.
[95]Li X. Q., Wen H. Y., Dong H. Q., et al., Chem. Commun.,2011,47,8647.
[96]Klaikherd A., Nagamani C., Thayumanavan S., J. Am. Chem. Soc.,2009,131,4830
[97]Sun H., Guo B., Cheng R., et al., Biomaterials,2009,30,6358.
[98]Li Y., Tong R., Xia H., et al., Chem. Commun.,2010,46,7739.
[99]Dong W. F., Kishimura A., Anraku Y., et al.,J. Am. Chem. Soc.,2009,131,3804.
[100]Ma N., Li Y., Xu H., et al., J. Am. Chem. Soc.,2010,132,442.
[101]Eloi J. C., Rider D. A., Cambridge G., et al.,J. Am. Chem. Soc.,2011,133,8903.
[102]Xiao Z. P., Cai Z. H., Liang H., et al.,J. Mater. Chem.,2010,20,8375
[103]Ercole F., Davis T. P., Evans R. A., Polym. Chem.,2010,1,37.
[104]Li M. H., Keller P., Soft Matter,2009,5,927.
[105]Han D., Tong X., Zhao Y., Macromolecules,2011,44,437
[106]Wang G., Tong X., Zhao Y., Macromolecules,2004,37,8911.
[107]Lee H., Wu W., Oh J. K., et al,Angew. Chem., Int. Ed,2007,46,2453.
[108]Jin Q., Liu G. Y., Ji J., J. Polym. Sci. Part A:Polym. Chem.,2010,48,2855.
[109]Tong X., Wang G., Soldera A., et al., J. Phys. Chem. B,2005,109,20281.
[110]Liu X. K., Jiang M.,Angew. Chem. Int. Ed.,2006,45,3846.
[111]Alvarez-Lorenzo C., Bromberg L., Concheiro A., Photochem. Photobiol,2009,85,848.
[112]Jiang J., Tong X., Zhao Y., J. Am. Chem. Soc.,2005,127,8290.
[113]Jiang J., Tong X., Morris D., et al., Macromolecules,2006,39,4633.
[114]Babin J., Pelletier M., Lepage M., et al.,Angew. Chem. Int. Ed.,2009,48,3329.
[115]Yan B., Boyer J. C., Branda N. R., et al.,J. Am. Chem. Soc.,2011,133,19714.
[116]Kirmse W., Eur. J. Org. Chem.,2002,14,2193.
[117]Andraos J., Kresge A. J., Popik V. V., J. Am. Chem. Soc.,1994,116,961.
[118]Urdabayev N. K., Popik V. V., J. Am. Chem. Soc.,2004,126,4058.
[119]Chen C. J., Liu G. Y., Liu X. S., et al., Polym. Chem.,2011,2,1389.
[120]Sun L., Yang Y., Dong C. M., et al., Small,2011,7,401.
[121]Jochum F. D., Theato P., Chem. Commun.,2010,46,6717.
[122]Khoukh S., Oda R., Labrot T., et al., Langmuir,2007,23,94.
[123]Ruchmann J., Fouilloux S., Tribet C., Soft Matter,2008,4,2098.
[124]Wang G., Tong X., Zhao Y., Macromolecules,2004,37,8911.
[125]Chen X., Hong L., You X., et al., Chem. Commun.,2009,1356.
[126]Inoue Y., Kuad P., Okumura Y., et al.,J. Am. Chem. Soc.,2007,129,6396.
[127]Tomatsu I., Hashidzume A., Harada A., J. Am. Chem. Soc.,2006,128,2226.
[128]Zou J., Guan B., Liao X., et al., Macromolecules,2009,42,7465.
[129]Jin Q., Liu G. Y., Liu X. S., et al, Soft Matter,2010,6,5589.
[130]Chen C. J., Liu G. Y., Liu X. S., et al. New J. Chem.,2012,36,694.
[131]Guo A., Liu G., Tao J., Macromolecules,1996,29,2487.
[132]Jiang J., Qi B., Lepage M., et al., Macromolecules,2007,40,790.
[133]He J., Tong X., Zhao Y, Macromolecules,2009,42,4845.
[134]Jin Q., Liu X. S., Liu G. Y., et al., Polymer,2010,51,1311.
[135]Jin Q., Luy C., Ji J., et al,J. Polym. Sci.:Part A:Polym. Chem.,2012,50,451.
[136]Shuai X. T., Ai H., Nasongkla N., et al,J. Control. Release,2004,98,415.
[137]Sinha V. R., Aggarwal A., Trehan A., Am. J. Drug Delivery,2004,2,157.
[138]Xu X. Y, Zhang X. F., Wang X. H., et al, Polym. Adv. Technol,2009,20,843.
[139]Harris J. M., Poly(ethylene glycol) chemistry:biotechnical and biomedical applications, Springer Us, New York, NY, USA 1992.
[140]Irvine D. J., Mayes A. M., Griffith C. L., Macromolecules,1996,29,6037.
[141]Li X., Ji J., Shen J., Polymer,2006,47,1984.
[142]Li X., Ji J., Shen J., Macromol. Rapid Commun.,2006,27,214.
[143]Li X., Ji J., Wang X., et al., Macromol. Rapid Commun.,2007.28.660.
[144]Ganta S., Devalapally H., Shahiwala A., et al.,J. Control. Release,2008,126,187.
[145]Almstead J. I. K., Urwyler B., Wirz J., J. Am. Chem. Soc.,1994.116,954.
[146]Fisher W. G., Partridge W. P., Dees C. et al. Photochem. Photobiol.1997.66,141.
[147]Goodwin A. P., Mynar J. L., Ma Y. Z., et al.,J. Am. Chem. Soc.,2005,127,9952.
[148]Mynar J. L., Goodwin A. P., Cohen J. A., et al., Chem. Commun.,2007,2081.
[149]Tian F., Yu Y. Y., Wang C. C., et al., Macromolecules,2008,41,3385.
[150]Yu Y. Y., Tian F., Wei C., et al., J. Polym. Sci. Part A:Polym. Chem.,2009,47,2763.
[151]Tian Y., Watanabe K., Kong X., et al., Macromolecules,2002,35,3739.
[152]Tong D., Yao J., Wang Q., et al., J. Appl Polym. Sci.,2009,114,1551.
[153]Jin Q., Lv L. P., Liu G. Y., et al., Polymer,2010,51,3068.
[154]Buback J., Kullmann M., Langhojer F., et al.,J. Am. Chem. Soc.,2010,132,16510.
[155]Rini M., Holm A. K., Nibbering E. T. J., et al., J. Am. Chem. Soc.,2003,125,3028.
[156]Bobrovsky A. Y., Boiko N. I., Shibaev V. P., Adv. Mater.,1999,11,1025.
[157]Vlassiouk I., Park C. D., Vail S. A., et al., Nano Lett.,2006,6,1013.
[158]Wagner K., Byrne R., Zanoni M., et al.,J. Am. Chem. Soc.,2011,133,5453.
[159]Huang C. Q., Wang Y., Hong C. Y., et al., Macromol. Rapid Commun.2011,32,1174.
[160]Liu J. Y., Huang W., Zhou Y. F., et al., Macromolecules,2009,42,4394.
[161]Liu J. Y., Huang W., Pang Y., et al., Biomacromolecules,2010,11,1564.
[162]Liu J. Y., Pang Y., Huang W., et al., Biomaterials,2010,31,1334.
[163]Liu J. Y., Huang W., Pang Y., et al., Biomaterials,2010,31,5643.
[164]Chen J., Zeng F., Wu S., et al., Chem. Eur. J.,2008,14,4851.
[165]Stolnik S., Illum L., Davis, S. S., Adv. Drug Delivery Rev.,1995,16,195.
[166]Mosqueria V. C. F., Legrand, P., Gulik A., et al., Biomaterials,2001,22,2967.
[2]Soussan E., Cassel S., Blanzat M., et al.,Angew. Chem. Int. Ed.,2009,48,274.
[3]Rijcken C. J. F., Soga O., Hennink W. E., et al.,J. Control. Release,2007,120,131.
[4]Lian T., Ho R. J. Y., J. Pharm. Sci.,2001,90,667.
[5]Gaucher G., Dufresne M. H., Sant V. P., et al., J. Control. Release,2005,109,69.
[6]Adams M. L., Lavasanifar A., Kwon G. S.,J. Pharm. Sci.,2003,92,1343.
[7]Discher D. E., Eisenberg A., Science,2002,297,967.
[8]Discher B. M., Won Y. Y., Ege D. S., et al., Science,1999,284,1143.
[9]Discher D. E., Ortiz V., Srinivas G., et al., Prog. Polym. Sci.,2007,32,838.
[10]Ramanan R. M. K., Chellamuthu P., Tang L. P., et al., Biotechnol. Prog.,2006,22,118.
[11]Wang J. J., Sung K. C., Hu O. Y. P., et al.,J. Control. Release,2006,115,140.
[12]Uekama K., Hirayama F., Irie T., Chem. Rev.,1998,98,2045.
[13]Bianco A., Kostarelos K., Prato M., Curr. Opin. Chem. Biol,2005,9,674.
[14]Gillies E. R., Frechet J. M. J., Drug Discovery Today,2005,10,35.
[15]Kwon G. S., Okano J.,Adv. Drug Delivery Rev.,1996,21,107.
[16]Rosier A., Vandermeulen G. W. M., Klok H. A., Adv. Drug Delivery Rev.,2001,53,95.
[17]Kataoka K., Harada A., Nagasaki Y., Adv. Drug Delivery Rev.,2001,47,113.
[18]Torchilin V. P., Cell. Mol Life Sci.,2004,61,2549.
[19]Gaucher G., Satturwar P., Jones M. C., et al., Eur. J. Pharm. Biopharm.,2010,76,147.
[20]Oerlemans C., Bult W., Bos M., et al, Pharm. Res.,2010,27,2569.
[21]Kedar U., Phutane P., Shidhaye S., et al,Nanomedicine:NBM,2010,6,714.
[22]Nishiyama N., Kataoka K., Pharmacol. Therap.,2006,112,630.
[23]Motornov M., Roiter Y., Tokarev I., et al, Prog. Polym. Sci.,2010,35,174.
[24]Jain S., Bates F. S., Science,2003,300,460.
[25]Sun J., Shi Q., Chen X. S., et al, Macromol Chem. Phys.,2008,209,1129.
[26]Zhang L. F., Eisenberg A., Polym. Adv. Technol,1998,9,677.
[27]Yu K., Eisenberg A., Macromolecules,1998,3,3509.
[28]Pochan D. J., Chen Z. Y.. Cui H. G., el al. Science,2004,306.94.
[29]Guo Z. P., Li Y. H., Tian H. Y.. et al, Langmuir,2009,25,9690.
[30]Soo P. L., Eisenberg A.,J. Polym. Sci., Part B:Polym. Phys.,2004,42,923.
[31]Blanazs A., Armes S. P., Ryan A. J., Macromol. Rapid Commun.,2009.30.267.
[32]Rodriguez-Hernandez J., Checot F., Gnanou Y., et al, Prog. Polym. Sci.,2005,30,691.
[33]Lonsdale D. E., Whittaker M. R., Monteiro M. J., J. Polym. Sci.:Parr A:Polym. Chem., 2009.47,6292.
[34]Francisa M. F., Pireddaa M., Winnika F. M., J. Controlled Release,2003,93,59.
[35]Brown M. D., Schatzlein A., Brownlie A., et al., Bioconjugate Chem.,2000,11,880.
[36]Cheng W. P., Gray A. I., Tetley L., et al, Biomacromolecules,2006,7,1509.
[37]Li C., Ge Z., Fang J., et al, Macromolecules,2009,42,2916.
[38]Thompson C. J., Ding C. X., Qu X. Z., et al, Colloid Polym. Sci.,2008,286,1511.
[39]Wang B. B., Zhang X., Jia X. R., et al., J. Polym. Sci.:Part A:Polym. Chem.,2005,43, 5512.
[40]Schenning A. P. H. J., Elissen-Roman C., Weener J. W., et al, J. Am. Chem. Soc.,1998, 120,8199.
[41]Cho B. K., Jain A., Nieberle J., et al, Macromolecules,2004,37,4227.
[42]Kim K. T., Winnik. M. A., Manners I., Soft Matter,2006,2,957.
[43]Gao C.. Yan D., Prog. Polym. Sci.,2004,29,183.
[44]Yan D., Zhou Y., Hou J., Science,2004,303,65.
[45]Zhou Y., Yan D., Angew. Chem. Int. Ed,2004,43,4896.
[46]Zhou Y., Yan D., Angew. Chem. Int. Ed,2005,44,3223.
[47]Zhou Y., Yan D., J. Am. Chem. Soc.,2005,127,10468.
[48]Zhou Y., Yan D., Chem. Commun.,2009,1172.
[49]Zhou Y., Huang W., Liu J., et al,Adv. Mater,2010,22,4567.
[50]del Barrio J., Oriol L., Sanchez C., et al., J. Am. Chem. Soc.,2010,132,3762.
[51]Khanna K., Varshney S., Kakkar A., Polym. Chem.,2010,1,1171.
[52]Gillies E. R., Frechet J. M. J., Bioconjugate Chem.,2005.16,361.
[53]Wang C. H., Wang C. H., Hsiue G. H., J. Control. Release,2005,108,140.
[54]Yao J., Ruan Y., Zhai T., et al. Polymer,2011,52,3396.
[55]Sun H., Guo B., Li X., et al., Biomacromolecules,2010,11,848
[56]Wang D., Yin J., Zhu Z. Y., et al., Macromolecules,2006,39,7378.
[57]Roy D., Cambre J. N., Sumerlin B. S., Chem. Commun.,2008,2477.
[58]Cheng C., Wei H., Shi B. X., et al., Biomaterials,2008,29,497.
[59]Nakayama M.; Okano T., Biomacromolecules,2005,6,2320
[60]Akimoto J., Nakayama M., Sakai K., et al, Biomacromolecules,2009,10,1331.
[61]Wang J., Pelletier M., Zhang H., et al, Langmuir,2009,25,13201.
[62]Kotharangannagari V. K., Sanchez-Ferrer A., Ruokolainen J., Macromolecules,2011,44, 4569.
[63]Yan Q., Hu J., Zhou R., et al., Chem. Commun.,2012,48,1913.
[64]Schumers J. M., Fustin C. A., Gohy J. F., Macromol Rapid Commun.,2010,31,1588.
[65]Zhao Y., J. Mater. Chem.,2009,19,4887.
[66]Schmaljohann D.,Adv. Drug. Delivery Rev,2006,58,1655.
[67]Grabe M., Oster G., J. Gen. Physiol,2001,117,329.
[68]Watson P., Jones A. T., Stephens D. J.,Adv. Drug Delivery Rev.,2005,57,43.
[69]Martin T. J., Prochazka K., Munk P., et al., Macromolecules,1996,29,6071.
[70]Liu S., Armes S. P., Angew. Chem. Int. Ed.,2002,41,1413.
[71]Liu S., Weaver J. V. M., Save M., et al., Langmuir,2002,18,8350.
[72]Liu S., Weaver J. V. M., Tang Y., et al., Macromolecules,2002,35,6121.
[73]Fujii S., Cai Y., Weaver J. V. M., et al.,J. Am. Chem. Soc.,2005,127,7304.
[74]Sumerlin B. S., Lowe A. B., Thomas D. B., et al., Macromolecules,2003,36,5982.
[75]Xu X., Smith A. E., Kirkland S. E., et al., Macromolecules,2008,41,8429.
[76]Bae Y., Fukushima S., Harada A., et al., Angew. Chem. Int. Ed.,2003,42,4640.
[77]Chen W., Meng F., Li F., et al, Biomacromolecules,2009,10,1727.
[78]Li Y., Lokitz B. S., McCormick C. L., Angew. Chem. Int. Ed.,2006,45,5792.
[79]Wei H., Cheng S. X., Zhang X. Z., et al.,Prog. Polym. Sci.,2009,34,893.
[80]Cui Q., Wu F., Wang E., J. Phys. Chem. B,2011,115,5913.
[81]Jochum F. D., Roth P. J., Kessler D., et al., Biomacromolecules,2010,11,2432.
[82]Feil H., Bae Y. H., Feijen J., et al., Macromolecules,1993,26,2496.
[83]Shibayama M., Mizutani S., Nomura S., Macromolecules,1996,29,2019.
[84]Cammas S., Suzuki K., Sone C., et al., J. Control. Release,1997,48,157
[85]Chung J. E., Yokoyama M., Yamato M., et al.,J. Control. Release,1999.62.115.
[86]Chung J. E., Yokoyama M., Okano T., J. Control. Release,2000,65,93.
[87]Nakayama M., Okano T., Miyazaki T., et al.,J. Control. Release,2006,115,46.
[88]Wei H., Zhang X. Z., Zhou Y., et al., Biomaterials,2006,27,2028.
[89]Wei H., Zhang X. Z., Cheng H., et al., J. Control. Release,2006,116,266.
[90]Chang C., Wei H., Feng J., et al., Macromolecul.es,2009,42,4838.
[91]Napoli A., Valentini M., Tirelli N., et al., Nat. Mater.,2004,3,183.
[92]Napoli A., Boerakker M. J., Tirelli N., et al., Langmuir,2004,20,3487.
[93]Ma N., Li Y., Ren H., et al., Polym. Chem.,2010,1,1609.
[94]Kakizawa Y., Harada A., Kataoka K., J. Am. Chem. Soc.,1999,121,11247.
[95]Li X. Q., Wen H. Y., Dong H. Q., et al., Chem. Commun.,2011,47,8647.
[96]Klaikherd A., Nagamani C., Thayumanavan S., J. Am. Chem. Soc.,2009,131,4830
[97]Sun H., Guo B., Cheng R., et al., Biomaterials,2009,30,6358.
[98]Li Y., Tong R., Xia H., et al., Chem. Commun.,2010,46,7739.
[99]Dong W. F., Kishimura A., Anraku Y., et al.,J. Am. Chem. Soc.,2009,131,3804.
[100]Ma N., Li Y., Xu H., et al., J. Am. Chem. Soc.,2010,132,442.
[101]Eloi J. C., Rider D. A., Cambridge G., et al.,J. Am. Chem. Soc.,2011,133,8903.
[102]Xiao Z. P., Cai Z. H., Liang H., et al.,J. Mater. Chem.,2010,20,8375
[103]Ercole F., Davis T. P., Evans R. A., Polym. Chem.,2010,1,37.
[104]Li M. H., Keller P., Soft Matter,2009,5,927.
[105]Han D., Tong X., Zhao Y., Macromolecules,2011,44,437
[106]Wang G., Tong X., Zhao Y., Macromolecules,2004,37,8911.
[107]Lee H., Wu W., Oh J. K., et al,Angew. Chem., Int. Ed,2007,46,2453.
[108]Jin Q., Liu G. Y., Ji J., J. Polym. Sci. Part A:Polym. Chem.,2010,48,2855.
[109]Tong X., Wang G., Soldera A., et al., J. Phys. Chem. B,2005,109,20281.
[110]Liu X. K., Jiang M.,Angew. Chem. Int. Ed.,2006,45,3846.
[111]Alvarez-Lorenzo C., Bromberg L., Concheiro A., Photochem. Photobiol,2009,85,848.
[112]Jiang J., Tong X., Zhao Y., J. Am. Chem. Soc.,2005,127,8290.
[113]Jiang J., Tong X., Morris D., et al., Macromolecules,2006,39,4633.
[114]Babin J., Pelletier M., Lepage M., et al.,Angew. Chem. Int. Ed.,2009,48,3329.
[115]Yan B., Boyer J. C., Branda N. R., et al.,J. Am. Chem. Soc.,2011,133,19714.
[116]Kirmse W., Eur. J. Org. Chem.,2002,14,2193.
[117]Andraos J., Kresge A. J., Popik V. V., J. Am. Chem. Soc.,1994,116,961.
[118]Urdabayev N. K., Popik V. V., J. Am. Chem. Soc.,2004,126,4058.
[119]Chen C. J., Liu G. Y., Liu X. S., et al., Polym. Chem.,2011,2,1389.
[120]Sun L., Yang Y., Dong C. M., et al., Small,2011,7,401.
[121]Jochum F. D., Theato P., Chem. Commun.,2010,46,6717.
[122]Khoukh S., Oda R., Labrot T., et al., Langmuir,2007,23,94.
[123]Ruchmann J., Fouilloux S., Tribet C., Soft Matter,2008,4,2098.
[124]Wang G., Tong X., Zhao Y., Macromolecules,2004,37,8911.
[125]Chen X., Hong L., You X., et al., Chem. Commun.,2009,1356.
[126]Inoue Y., Kuad P., Okumura Y., et al.,J. Am. Chem. Soc.,2007,129,6396.
[127]Tomatsu I., Hashidzume A., Harada A., J. Am. Chem. Soc.,2006,128,2226.
[128]Zou J., Guan B., Liao X., et al., Macromolecules,2009,42,7465.
[129]Jin Q., Liu G. Y., Liu X. S., et al, Soft Matter,2010,6,5589.
[130]Chen C. J., Liu G. Y., Liu X. S., et al. New J. Chem.,2012,36,694.
[131]Guo A., Liu G., Tao J., Macromolecules,1996,29,2487.
[132]Jiang J., Qi B., Lepage M., et al., Macromolecules,2007,40,790.
[133]He J., Tong X., Zhao Y, Macromolecules,2009,42,4845.
[134]Jin Q., Liu X. S., Liu G. Y., et al., Polymer,2010,51,1311.
[135]Jin Q., Luy C., Ji J., et al,J. Polym. Sci.:Part A:Polym. Chem.,2012,50,451.
[136]Shuai X. T., Ai H., Nasongkla N., et al,J. Control. Release,2004,98,415.
[137]Sinha V. R., Aggarwal A., Trehan A., Am. J. Drug Delivery,2004,2,157.
[138]Xu X. Y, Zhang X. F., Wang X. H., et al, Polym. Adv. Technol,2009,20,843.
[139]Harris J. M., Poly(ethylene glycol) chemistry:biotechnical and biomedical applications, Springer Us, New York, NY, USA 1992.
[140]Irvine D. J., Mayes A. M., Griffith C. L., Macromolecules,1996,29,6037.
[141]Li X., Ji J., Shen J., Polymer,2006,47,1984.
[142]Li X., Ji J., Shen J., Macromol. Rapid Commun.,2006,27,214.
[143]Li X., Ji J., Wang X., et al., Macromol. Rapid Commun.,2007.28.660.
[144]Ganta S., Devalapally H., Shahiwala A., et al.,J. Control. Release,2008,126,187.
[145]Almstead J. I. K., Urwyler B., Wirz J., J. Am. Chem. Soc.,1994.116,954.
[146]Fisher W. G., Partridge W. P., Dees C. et al. Photochem. Photobiol.1997.66,141.
[147]Goodwin A. P., Mynar J. L., Ma Y. Z., et al.,J. Am. Chem. Soc.,2005,127,9952.
[148]Mynar J. L., Goodwin A. P., Cohen J. A., et al., Chem. Commun.,2007,2081.
[149]Tian F., Yu Y. Y., Wang C. C., et al., Macromolecules,2008,41,3385.
[150]Yu Y. Y., Tian F., Wei C., et al., J. Polym. Sci. Part A:Polym. Chem.,2009,47,2763.
[151]Tian Y., Watanabe K., Kong X., et al., Macromolecules,2002,35,3739.
[152]Tong D., Yao J., Wang Q., et al., J. Appl Polym. Sci.,2009,114,1551.
[153]Jin Q., Lv L. P., Liu G. Y., et al., Polymer,2010,51,3068.
[154]Buback J., Kullmann M., Langhojer F., et al.,J. Am. Chem. Soc.,2010,132,16510.
[155]Rini M., Holm A. K., Nibbering E. T. J., et al., J. Am. Chem. Soc.,2003,125,3028.
[156]Bobrovsky A. Y., Boiko N. I., Shibaev V. P., Adv. Mater.,1999,11,1025.
[157]Vlassiouk I., Park C. D., Vail S. A., et al., Nano Lett.,2006,6,1013.
[158]Wagner K., Byrne R., Zanoni M., et al.,J. Am. Chem. Soc.,2011,133,5453.
[159]Huang C. Q., Wang Y., Hong C. Y., et al., Macromol. Rapid Commun.2011,32,1174.
[160]Liu J. Y., Huang W., Zhou Y. F., et al., Macromolecules,2009,42,4394.
[161]Liu J. Y., Huang W., Pang Y., et al., Biomacromolecules,2010,11,1564.
[162]Liu J. Y., Pang Y., Huang W., et al., Biomaterials,2010,31,1334.
[163]Liu J. Y., Huang W., Pang Y., et al., Biomaterials,2010,31,5643.
[164]Chen J., Zeng F., Wu S., et al., Chem. Eur. J.,2008,14,4851.
[165]Stolnik S., Illum L., Davis, S. S., Adv. Drug Delivery Rev.,1995,16,195.
[166]Mosqueria V. C. F., Legrand, P., Gulik A., et al., Biomaterials,2001,22,2967.