基于双亲缩肽嵌段共聚物纳米粒的制备及其在药物缓控释研究中的应用
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
性能稳定、结构可调的双亲可生物降解嵌段共聚物能自组装形成疏水核-亲水壳的纳米微球,因此其在药物缓释领域得到研究者的极大关注。本文以吗啉-2,5-二酮衍生物为研究对象,采用开环聚合(ROP)及原子转移自由基聚合(ATRP)技术构建一系列新型缩肽两亲嵌段共聚物,并对其进行药物缓控释研究。主要成果概括如下:
     1.在成功制备吗啉-2,5-二酮衍生物即3(S)-甲基-吗啉-2,5-二酮(MMD)、3(S)-正丁基-吗啉-2,5-二酮(SBMD)、3(S)-异丁基-吗啉-2,5-二酮(IBMD)以及脂肪族聚酯聚对二氧环己酮PPDO(以备后期嵌段共聚物的表征)后,首先分别以MMD及SBMD为单体,结合PDO及聚乙二醇(PEG)采用ROP技术合成双亲三嵌段共聚物,即P(MMD-co-PDO)-b-PEG-b-P(MMD-co-PDO)(PMMD-PPDO-PEG)及P(SBMD-co-PDO)-b-PEG-b-P(SBMD-co-PDO)(PSBMD-PPDO-PEG)。通过核磁共振氢谱碳谱(1H NMR,13C NMR),傅里叶红外光谱(FT-IR),凝胶渗透光谱(GPC),差热扫描热力学(DSC)测试及热重分析(TGA)等对以上双亲三嵌段共聚物的结构成功表征。
     2.基于IBMD, PDO及PEG开环聚合合成P(IBMD-co-PDO)-b-PEG-b-P(IBMD-co-PDO)(PIBMD-PPDO-PEG),将其与溴代异丁酰溴反应合成大分子引发剂,然后与亲水性的甲基丙烯酸二甲氨基乙酯(DMAEMA)通过原子转移自由基聚合即ATRP反应构建以聚缩肽为基础的新型双亲五嵌段共聚物PDMAEMA-b-P(IBMD-co-PDO)-b-PEG-b-P(IBMD-co-PDO)-b-PDMAEMA(PDMAEMA-PIBMD-PPDO-PEG)。对以上双亲五嵌段共聚物的结构进行1H NMR,13C NMR,FT-IR,GPC,DSC及TGA表征。
     3.分别以合成的双亲三嵌段共聚物PMMD-PPDO-PEG及PSBMD-PPDO-PEG为载体,阿霉素(DOX)为模型药物,采用乳化溶剂挥发扩散法(O/W)制备空白及载药微球(药物DOX与嵌段共聚物之间通过氢键作用及疏水效应结合)。对空白共聚物微球进行体外降解实验分析,临界胶束浓度CMC(芘荧光探针法)及Zeta电位测试。实验研究表明两种共聚物很容易在PBS内形成均匀统一的纳米微球,其共聚物微球的数均分子量(Mn)均随降解时间的增加而逐渐减小。基于MMD的两亲三嵌段共聚物的CMC测试结果表明共聚物PMMD-PPDO-PEG微球较稳定,CMC值在0.41-0.66μg/mL之间并且其值基本随进料中PDO含量的升高而增大。基于SBMD的三嵌段共聚物微球的Zeta电位测试表明共聚物微球具有较好的稳定性。空白及载DOX聚合物(PMMD-PDO-PEG及PSBMD-PPDO-PEG)微球的动态光散射仪(DLS)与透射电镜(TEM)测试结果表明,两系列共聚物在PBS中自组装形成的胶束粒子呈椭圆形单分布,颗粒分散较均匀,其平均粒径分别为100和200nm。除此,两系列共聚物均具有良好的载药量(LC),包封率(EE)及药物缓释行为。
     4.制备双亲五嵌段ATRP共聚物纳米微球,分别以布洛芬(IBU)及IBU-DOX组合作为模型药物对共聚物微球的LC,EE及体外释放行为进行考察。测试结果均表明,载药时随模型药物投入量的增加,聚合物LC及EE相应增加,但药物(IBU,IBU-DOX)与共聚物投入质量到达一定比例(即16/44,8-8/44)后LC及EE降低,载IBU的共聚物微球,其LC和EE稍高于载IBU-DOX的共聚物微球。而且制备的聚合物微球LC和EE均与PBS浓度有关。同时,本实验选取不同pH值(5.0,7.4)的PBS溶液作为释放介质进一步考察载药微球的体外释放特征,结果表明载IBU-DOX的共聚物微球具有很好的pH响应性,低pH下IBU-DOX释放速度较快,可能由于PDMAEMA和DOX上氨基的质子化以及微球核心的快速降解所致。此外实验结合DLS及TEM探究了该系列共聚物在PBS中自组装情况、载药聚合物微球的形态及粒径分布。聚合物PDMAEMA-PIBMD-PPDO-PEG微球的DLS测试结果表明载有IBU及IBU-DOX的纳米颗粒呈圆形均匀分布,其粒径在100nm左右,而且所有载药后的共聚物微球粒径均稍有增加。由以上表征结果可以设想其共聚物系统将是很有潜力的药物控释载体。
Biodegradable amphiphilic block copolymers with stable performance andadjustable structure can self-assemble into hydrophobic core and hydrophilic shellnanomicrospheres, thus they have aroused the great concern of researchers in drugdelivery field. In this paper, morpholine-2,5-dione derivatives containing depsipeptidestructure were deemed as the research objects, a series of novel amphiphilicdepsipeptide block copolymers were constructed by using the ring-openingpolymerization (ROP) and atom transfer radical polymerization (ATRP) technology,meanwhile, the drug release behavior was also studied. The main results aresummarized as follows:
     1. After successfully preparing morpholine-2,5-dione derivatives, i.e.3(S)-methyl-morpholine-2,5-dione(MMD),3(S)-butyl-morpholine-2,5-monomers,3(S)-isobutyl-morpholino-2,5-dione (IBMD) and aliphatic polyesters poly(p-dioxanone)(PPDO)(Mentioned here, in order to characterize the latter block copolymers). Twokinds of amphiphilic triblock copolymers {i.e.poly(3(S)-methyl-morpholine-2,5-dione-co-p-dioxanone)-block-poly(ethylene glycol)6000-block-poly(3(S)-methyl-morpholine-2,5-dione-co-p-dioxanone)[P(MMD-co-PDO)-b-PEG-b-P(MMD-co-PDO)](PMMD-PPDO-PEG) andpoly(3(S)-butyl-morpholine-2,5-dione-co-p-dioxanone)-block-poly(ethylene glycol)6000-block-poly(3(S)-butyl-morpholine-2,5-dione-co-p-dioxanone)[P(SBMD-co-PDO)-b-PEG-b-P(SBMD-co-PDO)](PSBMD-PPDO-PEG)} which werebased on morpholine-2,5-dione derivatives (MMD and SBMD, respectively), andcombined with PDO and polyethylene glycol (PEG), were synthesized by utilizing thering-opening polymerization (ROP) technique. The structural characteristics of theabove amphiphilic block copolymers were identified by using1H NMR, FT-IR, GPC,DSC and TGA analysis.
     2. Another ABA triblock copolymers ofpoly(3(S)-isobutyl-morpholine-2,5-dione-co-p-dioxanone)-block-poly(ethylene glycol)6000-block-poly(3(S)-isobutyl-morpholine-2,5-dione-co-p-dioxanone)[P(IBMD-co-PDO)-b-PEG-b-P(IBMD-co-PDO)] were successfully prepared by ROP of3(S)-isobutyl-morpholine-2,5-dione (IBMD) and p-dioxanone (PDO) using PEG6000asinitiator. And then the macroinitiatorsBr-P(IBMD-co-PDO)-b-PEG-b-P(IBMD-co-PDO)-Br were prepared from them by the bromination with2-bromoisobutyryl bromide (BiBB). Finally, hydrophilicpoly(2-(dimethylamino)ethyl methacrylate)(PDMAEMA) blocks were attached to thesehydrophobic triblock copolymers by ATRP, and the amphiphilic multiblock copolymerswere defined asPDMAEMA-b-P(IBMD-co-PDO)-b-PEG-b-P(IBMD-co-PDO)-b-PDMAEMA(PDMAEMA-PIBMD-PPDO-PEG). The structures of the above copolymers were characterizedby using1H NMR,13C NMR, FT-IR, GPC, DSC and TGA analysis.
     3. Taking the synthetic triblock copolymers PMMD-PPDO-PEG andPSBMD-PPDO-PEG as carriers, doxorubicin (DOX) as model drugs, the blank anddrug-loaded microspheres were prepared by an oil-in water (o/w) emulsion solventevaporation method (through the combination of hydrogen bond and hydrophobic effectbetween DOX and block copolymers), those blank copolymer microspheres werecharacterized by hydrolytic degradation analysis, the critical micellar concentration(CMC)(fluorescene probe method of pyrene)and Zeta potential. Experiments studiesshowed that the copolymers could easily form uniform microspheres in phosphatebuffered solution (PBS), and the number-average molecular weight (Mn) of those blockcopolymers decreased along with degradation time. Copolymer PMMD-PPDO-PEGself-assembled into stable nanosized microspheres with CMC of0.41-0.66μg/mL.Basically, the CMC of microspheres increased slightly with the increase of PDO in feed.Zeta potential measurement of the copolymer microspheres based on SBMD and IBMDindicated that the copolymer microspheres had good stability. The dynamic lightscattering (DLS) and transmission electron microscopy (TEM) results of blank andDOX-loaded copolymers (PMMD-PPDO-PEG and PSBMD-PPDO-PEG) microspheresshowed that the two series of copolymers in PBS self-assembled uniform, dispersed,ellipsoidal and single distribution nanoparticles. The average diameter of the particleswere100and200nm, respectively. In addition, they exhibited high drug loadingcapacity (LC), the encapsulation efficiency (EE) and sustained drug release behavior inPBS.
     4. Preparing amphiphilic multiblock ATRP copolymers nanomicrospheres,Ibuprofen (IBU) and the combination of IBU-DOX were chosen as model drugs, the LC,EE and the drug release behavior of the multiblock copolymers microspheres wereinvestigated. The tests showed that LC and EE increased with increasing the initialweight ratios of drug to copolymer, but LC and EE decreased after the ratio increased toa certain percentage (16/44and8-8/44, respectively). The LC and EE of the IBU-loadedcopolymer microspheres are slightly higher than that of IBU-DOX-loaded copolymer microspheres. Moreover, LC and EE of the prepared copolymer microspheres arecorrelated with PBS concentration. Meanwhile, we selected PBS of different pH (5.0,7.4) as the release media to further investigate the characteristics of drug-loadedmicrospheres. The results showed that IBU-DOX-loaded copolymer microspheres hadgood pH-responsiveness. The drug release rate of copolymer microspheres in low pH(5.0) was faster than that in pH (7.4), which is likely due to the protonation of the aminogroups of PDMAEMA and DOX, and fast degradation of microsphere core. In addition,experiments explored the self-assembly conditions of the copolymers, the microspheresmorphology of drug-loaded copolymers and particle size distribution through DLS andTEM measurements. The DLS results of PDMAEMA-PIBMD-PPDO-PEGmicrospheres showed that the IBU-and IBU-DOX-loaded nanoparticles werewell-defined uniform spherical particles with diameter about100nm. All copolymermicrospheres size increased slightly after drug loading. From the above results, it can beenvisaged that these copolymer systems are promising candidates for controlled releaseapplication.
引文
[1] Green J. J., Zhou B. Y., Mitalipova M. M. et al. Nanoparticles for gene transfer tohuman embryonic stem cell colonies. Nano Letters,2008(10),8:3126-3130.
    [2] Battig A., Hiebl B., Feng Y. K. et al. Biological evaluation of degradable,stimuli-sensitive multiblock copolymers having polydepsipeptide-andpoly(epsilon-caprolactone) segments in vitro. Clinical Hemorheology andMicrocirculation,2011,48:161-172.
    [3].戈进杰.生物降解高分子材料及其应用.北京:化学工业出版社,2002.
    [4].汪连生.新型生物可降解聚碳酸酯及其共聚物的合成与性能研究.武汉:武汉大学,2004.
    [5] Lim S. K., Lee S. I., Jang S. G. et al. Synthetic aliphatic biodegradablepoly(Butylene Succinate)/MWNT nanocomposite foams and their physicalcharacteristics. Journal of Macromolecular Science, Part B: Physics,2011,50(6):1171-1184.
    [6] Feng Y. K., Guo J. T. Biodegradable polydepsipeptides. International Journal ofMolecular Sciences,2009,10:589-615.
    [7] Borner H.G. Functional polymer-bioconjugates as molecular LEGO bricks.Macromolecular Chemistry and Physics,2007,208:124-130.
    [8] Zhu C.H., Chen Q., Tian W.W. et al. Mater. Rev.,2004,18(7):96-98.
    [9] Zhao Y. C., Hu Y. J., Cheng S. J. et al. Degradation of morpholine-2,5-dionederivative copolymer in vitro. Polymer Bulletin,2008,61:35-41.
    [10] Liu J., Jiang Z. Z., Zhang S. M. et al. Biodegradation, biocompatibility, and drugdelivery in poly (omega-pentadecalactone-co-p-dioxanone) copolyesters. Biomaterials,2011,32:6646-6654.
    [11] Feng Y. K., Lu J., Behl M. et al. Progress in depsipeptide-based biomaterials.Macromolecular Bioscience,2010,10:1008-1021.
    [12] Feng, Y. K.[M]. Germany: Shaker Verlag GmbH,2001.
    [13] Cao S. W., Zhu Y. J., Wu J. et al. Preparation and sustained-release property oftriblock copolymer/calcium phosphate nanocomposite as nanocarrier for hydrophobicdrug. Nanoscale Research Letters,2010,5:781-785.
    [14] Giacomelli C., Schmidt V., Borsali R. Specific interactions improve the loadingcapacity of block copolymer micelles in aqueous media. Langmuir2007,23:6947-6955.
    [15] Zhang Y., Chen J. J., Zhang G. H. et al. Sustained rrelease of ibuprofen frompolymeric micelles with a high loading capacity of ibuprofen in media simulatinggastrointestinal tract fluids. Reactive&Functional Polymers,2012,72:359-364.
    [16] Ruenraroengsak P., Cook J. M., Florence A. T. Nanosystem drug targeting: facingup to complex realities. Journal of Controlled Release,2010,141:265-276.
    [17] Gou P. F., Zhu W. P., Shen Z. Q. Synthesis, Self-assembly, and drug-loadingcapacity of well-defined cyclodextrin-centered drug-conjugated amphiphilic A(14)B(7)miktoarm star copolymers based on poly(epsilon-caprolactone) and poly(ethyleneglycol). Biomacromolecules,2010,11:934-943.
    [18] Ho K. M., Li W. Y., Wong C. H. et al. Amphiphilic polymeric particles withcore-shell nanostructures: emulsion-based syntheses and potential applications.Colloid Polymer Science,2010,288:1503-1523.
    [19] Shanmugananda Murthy K., Ma Q. G., Clark Jr. C. G. et al. Fundamental designaspects of amphiphilic shell-crosslinked nanoparticles for controlled releaseapplications. Chemical Communications.2001,0:773-774.
    [20] Becker M. L., Remsen E. E., Wooley K. L. Diblock copolymers, micelles, andshell-crosslinked nanoparticles containing poly(4-fluorostyrene): tools for detailedanalyses of nanostructured materials. Journal of Polymer Science Part A-PolymerChemistry,2001,39:4152-4166.
    [21] Kohler. N., Fryxell G. E., Zhang M. Q. A bifunctional poly(ethylene glycol)silane immobilized on metallic oxide-based nanoparticles for conjugation with celltargeting agents. Jounal of the American Chemical Society,2004,126:7206-7211.
    [22] Jeetah R., Luximon A. B., Jhurry D. New amphiphilic PEG-b-P(ester-ether)micelles as potential drug nanocarriers. Journal of Nanoparticle Research,2012,14:1168.
    [23] Avgoustakisa K., Beletsi A., Panagi Z. et al. PLGA–mPEG nanoparticles ofcisplatin: in vitro nanoparticle degradation, in vitro drug release and in vivo drugresidence in blood properties. Journal of Controlled Release,2002,79:123-135.
    [24] Liu G. J., Ma S. B., Li S. K. et al. The highly efficient delivery of exogenousproteins into cells mediated by biodegradable chimaeric polymersomes. Biomaterials,2010,31:7575-7585.
    [25] Heffernan M. J., Murthy N. Polyketal Nanoparticles: A new pH-sensitivebiodegradable drug delivery vehicle. Bioconjugate chemistry,2005,16:1340-1342.
    [26] Chang J. H., An Y. U., Sur G. S. Poly(lactic acid) nanocomposites with variousorganoclays. I. thermomechanical properties, morphology, and gas permeability.Journal of Polymer Science: Part B: Polymer Physics,2003,41:94-103.
    [27] Cohen S., Yoshioka T., Lucarelli M. Controlled delivery systems for proteinsbased on poly(lactic/glycolic acid) microspheres. Pharmaceutical Research,1991,8(6):713-720.
    [28] Xiao L., Xiong X. Q., Sun X. H. et al. Role of cellular uptake in the reversal ofmultidrug resistance by PEG-b-PLA polymeric micelles. Biomaterials,2011,32(22):5148-5157.
    [29] Wang B., Jiang W. M., Yan H. Novel PEG-graft-PLA nanoparticles with thepotential for encapsulation and controlled release of hydrophobic and hydrophilicmedications in aqueous medium. International Journal of Nanomedicine,2011,6:1443-1453.
    [30] Feng Y. K., Klee D., H cker H. et al. Lipase-catalyzed ring-openingpolymerization of6(S)-methyl-morpholine-2,5-dione. Journal of Polymer SciencePart A-Polymer Chemistry,2005,43:3030-3039.
    [31] Feng Y. K., Behl M., Kelch S. et al. Biodegradable multiblock copolymers basedon oligodepsipeptides with shape-memory properties. Macromolecular Bioscience,2009,9:45-54.
    [32] Wu Y. Q., Mackay A., Mcdaniel J. R. et al. Fabrication of elastin-like polypeptidenanoparticles for drug delivery by electrospraying. Biomacromolecules,2009,10:19-24.
    [33] Zhu C. H., Jung S., Luo S. B. et al. Co-delivery of siRNA and paclitaxel intocancer cells by biodegradable cationic micelles based onPDMAEMA-PCL-PDMAEMA triblock copolymers. Biomaterials,2010,31:2408-2416.
    [34] Ueki K., Onishi H., Sasatsu M. et al. Preparation of carboxy-PEG-PLAnanoparticles loaded with camptothecin and their body distribution in solidtumor-bearing mice. Drug Development Research,2009,70:512-519.
    [35] Katsarava R., Beridze V., Arabuli N. et al. Amino acid-based bioanalogouspolymers. Synthesis, and study of regular poly(ester amide)s based onbis(alpha-amino acid) alpha,omega-alkylene diesters, and aliphatic dicarboxylic acids.Journal of Polymer Science Part A-Polymer Chemistry,1999,37(4):391-407.
    [36] Feng Y. K., Lu J., Behl M. et al. Progress in depsipeptide-based biomaterials.Macromolecular Bioscience,2010,10:1008-1021.
    [37] Feng Y. K., Klee D., Keul, H. et al. Synthesis and characterization of new ABAtriblock copolymers with poly[3(S)-isobutylmorpholine-2,5-dione] and poly(ethyleneoxide) blocks. Macromolecular Chemistry and Physics.1999,200:2276-2283.
    [38] Kataoka K., Harada A., Nagasaki Y. Block copolymer micelles for drugdelivery: design, characterization and biological significance. Advanced DrugDelivery Reviews,2001,47:113-131.
    [39] Fan Y. J., Chen G. P., Tananka J. et al. Biosynthesis of polyamides containingamino acid residues through the specific aminolysis of amino acid ester derivatives.Materials Science&Engineering C-Biomimetic and Supramolecular Systems,2004,24:791-796.
    [40] Li Y. Z., He J. D., Cui G. Z. et al. Synthesis ofpolymorpholine-2,5-dione-block-polylactide by two-step anionic ring-openingpolymerization. Journal of Applied Polymer Science,2010,118:2005-2008.
    [41] Chen S. C., Zhou Z. X., Wang Y. Z. et al. A novel biodegradablepoly(p-dioxanone)-grafted poly(vinyl alcohol) copolymer with a controllable in vitrodegradation. Polymer,2006,47:32-36.
    [42] Liu G. Y., Zhai Y. L., Wang X. L. et al. Preparation, characterization, and in vitrodrug release behavior of biodegradable chitosan-graft-poly(1,4-dioxan-2-one)copolymer. Carbohydrate Polymers,2008,74:862-867.
    [43] Behl M., Ridder U., Feng Y. K. et al. Shape-memory capability of binarymultiblock copolymer blends with hard and switching domains provided by differentcomponents. Soft Matter,2009,5:676-684.
    [44] Bhattarai. N., Cha. D. I., Bhattarai. S. R. et al. Biodegradable electrospun mat:Novel block copolymer of poly (p-dioxanone-co-L-lactide)-block-poly(ethyleneglycol). Journal of Polymer Science Part B: Polymer Physics,2003,41:1955-1964.
    [45] Bhattarai S. R., Bhattarai N., Yi H. K. Novel biodegradable electrospunmembrane: scaffold for tissue engineering. Biomaterials,2004,25:2595-2602.
    [46] Hong J. T., Cho, N. S., Yoon H. S. et al. Preparation and characterization ofbiodegradable poly(trimethylenecarbonate-ε-caprolactone)-block-poly(p-dioxanone)copolymers. Journal of Polymer Science Part A: Polymer Chemistry,2005,43:2790-2799.
    [47] Ding S. D., Liu Z. P., Yang T. et al. Effect of polycarbodiimide on the thermalstability and crystallization of poly(p-dioxanone). Journal of Polymer Research,2010,17:63-70.
    [48] Quan S. L., Kang S. G., Qiu Z. C. et al. Characterization of electrospunpoly(p-dioxanone) and poly(p-dioxanone)/clay nanocomposite fibers. Journal ofNanoscience and Nanotechnology,2011,11:1609~1612.
    [49] Zhu J., Dang H. C., W W. T. et al. Cellulose diacetate-g-poly(p-dioxanone)co-polymer: synthesis, properties and microsphere preparation. Journal ofBiomaterials Science, Polymer Edition,2011,22:981-999.
    [50] Li Y., Wang X. L., Yang K. K. et al. A rapid synthesis of poly (p-dioxanone) byring-opening polymerization under microwave irradiation. Polymer Bulletin.2006,57:873-880.
    [51] Uhrich K. E., Cannizzaro S. M., Langer R. S. et al. Polymeric systems forcontrolled drug release. Chemical Reviews,1999,99:3181-3198.
    [52] Zelikin A. N. Drug releasing polymer thin films: new era of surface-mediateddrug delivery. ACS Nano,2010,4:2494-2509.
    [53] Zou W. W., Liu C. X., Chen Z. J. et al. Preparation and characterization ofcationic PLA-PEG nanoparticles for delivery of plasmid DNA. Nanoscale ResearchLetters,2009,4:982-992.
    [54] Elsabahy M., Wooley K. L. Strategies toward well-defined polymer nanoparticlesinspired by nature: Chemistry versus versatility. Journal of Polymer Science PartA-Polymer Chemistry,2012,50:1869-1880.
    [55] Van Berkel K. Y., Hawker C. J. Tailored composite polymer–metal nanoparticlesby miniemulsion polymerization and thiol-ene functionalization. Journal of PolymerScience Part A: Polymer Chemistry.2010,48:1594-1606.
    [56] Lundberg B. B. Preparation and characterization of polymeric pH-sensitiveSTEALTH (R) nanoparticles for tumor delivery of a lipophilic prodrug of paclitaxel.International Journal of Pharmaceutics,2011,408:208-212.
    [57] Xiao K., Luo J. T., Fowler W. et al. A self-assembling nanoparticle for paclitaxeldelivery in ovarian cancer. Biomaterials,2009,30:6006-6016.
    [58] Ganta S., Devalapally H., Shahiwala A. et al. A review of stimuli-responsivenanocarriers for drug and gene delivery. Journal of Controlled Release,2008,126:187-204.
    [59] McDaniel J. R., Callahan D. J., Chilkoti A. Drug delivery to solid tumors byelastin-like polypeptides. Advanced Drug Delivery Reviews,2010,62:1456-1467.
    [60] Elsabahy M., Wooley K. L. Strategies toward well-defined polymer nanoparticlesinspired by nature: Chemistry versus versatility. Journal of Polymer Science Part A:Polymer Chemistry.2012,50:1869-1880.
    [61] Hoshino Y., Koide H., Urakami T. Recognition, neutralization, and clearance oftarget peptides in the bloodstream of living mice by molecularly imprinted polymernanoparticles: a plastic antibody. Journal of the American Chemical Society,2010,132:6644-6645.
    [62] Meng F. H., Zhong Z. Y., Feijen J. Stimuli-responsive polymersomes forprogrammed drug delivery. Biomacromolecules,2009,10:197-209.
    [63] Cheng R., Meng F. H., Deng C. et al. Dual and multi-stimuli responsivepolymeric nanoparticles for programmed site-specific drug delivery. Biomaterials,2013,34:3467-3657.
    [64] Shen M., Huang Y. Z., Han L. M. et al. Multifunctional drug delivery system fortargeting tumor and its acidic microenvironment. Journal of Controlled Release,2012,3:884-892.
    [65] Vigliotta G., Mella M., Rega D. et al. Modulating antimicrobial activity bysynthesis: dendritic copolymers based on nonquaternized2-(Dimethylamino)ethylmethacrylate by Cu-mediated ATRP. Biomacromolecules,2012,13:833-841.
    [66] Shim Y. H., Bougard F., Coulembier O. et al. Synthesis and characterization oforiginal2-(dimethylamino)ethyl methacrylate/poly(ethyleneglycol) star-copolymers.European Polymer Journal,2008,44:3715-3723.
    [67] Patten T. E., Matyjaszewski K. Atom transfer radical polymerization and thesynthesis of polymeric materials. Advanced Materials,1998,10:901-915.
    [68] Kricheldorf H. R., Hauser K. Polylactones,45-Homo-and copolymerizations of3-methylmorpholine-2,5-dione initiated with a cyclic tin alkoxide. MacromolecularChemistry and Physics,2001,202:1219-1226.
    [69] Feng Y. K., Doris K., Hartwig H., Lipase Catalyzed Copolymerization of3(S)-Isopropylmorpholine-2,5-dione and D,L-Lactide, Macromolecular Bioscience,2001,4:587-590.
    [70] Feng Y. K., Klee D., Keul H. et al. Synthesis and characterization of new blockcopolymers with poly(ethylene oxide) and poly[3(S)-sec-butylmorpholine-2,5-dione]sequences, Macromolecular Bioscience,2001,1:30-39.
    [71] J rres V., Keul H., H cker H. Polymerization of(3S,6S)-3-isopropyl-6-methyl-2,5-morpholine dione with tin octoate and tinacetylacetonate. Macromolecular Chemistry and Physics,1998,199:835-843.
    [72] Feng Y. K., Klee D., H cker H. Synthesis and characterization of new ABAtriblock copolymers with poly[3(S)-isobutylmorpholine-2,5-dione] and poly(ethyleneoxide) blocks. Macromolecular Chemistry and Physics,1999,200:2276-2283.
    [73] You Z. W., Cao H. P., Gao J. et al. A functionalizable polyester with freehydroxyl groups and tunable physiochemical and biological properties. Biomaterials,2010,31:3129-3138.
    [74] Freichels1H., Pourcelle V., Le Duff C. S.“Clip” and “Click” chemistriescombination: toward easy PEGylation of degradable aliphatic polyesters.Macromolecular Rapid Communications.2011,32:616-621.
    [75] Zhu J., Wang W. T., Wang X. L. et al. Green synthesis of a novel biodegradablecopolymer base on cellulose and poly(p-dioxanone) in ionic liquid. CarbohydratePolymers,2009,76:139-144.
    [76] Huang H. X., Yang K. K., Wang Y. Z. et al. Synthesis, characterization, andthermal properties of a novel pentaerythritol-initiated star-shaped poly(p-dioxanone).Journal of Polymer Science Part A-Polymer Chemistry,2006,44:1245-1251.
    [77]杨科坷.基于对二氧环己酮脂肪族聚酯的合成与结构性能研究.四川成都:四川大学,2003.
    [78]王玉忠.一种用于制备对二氧环己酮的催化剂:中国.专利200510021203. X.2005-07-01.
    [79] Park E. K., Kim S. Y., Lee S. B. et al. Folate-conjugated methoxy poly(ethyleneglycol)/poly(epsilon-caprolactone) amphiphilic block copolymeric micelles fortumor-targeted drug delivery. Journal of Controlled Release,2005,109:158-168.
    [80] Aryal S., Jack Hu C. M., Zhang L. F. Polymer-Cisplatin conjugate nanoparticlesfor acid-responsive drug delivery. Acs Nano,2010,4:251-258.
    [81] Oh J. K. Polylactide (PLA)-based Amphiphilic block copolymers: synthesis,self-assembly, and biomedical applications. Soft Matter,2011,7:5096-5108.
    [82] Ouchi T., Miyazaki H., Arimura H. et al. Formation of polymeric micelles withamino surfaces from amphiphilic AB-type diblock copolymers composed ofpoly(glycolic acid lysine) segments and polylactide segments. Journal of PolymerScience Part A-Polymer Chemistry,2002,40:1426-1432.
    [83] Zhang Y., Chen J. J., Zhang G. H. et al. Sustained release of ibuprofen frompolymeric micelles with a high loading capacity of ibuprofen in media simulatinggastrointestinal tract fluids. Reactive&Functional Polymers,2012,72:359-364.
    [84] Tian W. W., Chen Q., Yu C. H. et al. Amino-terminated poly(ethylene glycol) asthe initiator for the ring-opening polymerization of3-methylmorpholine-2,5-dione.European Polymer Journal,2003,39:1935-1938.
    [85] Liu G. Y., Chen C. J., Ji J. Biocompatible and biodegradable polymersomes asdelivery vehicles in biomedical applications. Soft Matter,2012,8:8811-8821.
    [86] Qi R. G., Liu S., Chen J. et al. Biodegradable copolymers with identical cationicsegments and their performance in siRNA delivery. Journal of Controlled Release,2012,159:251-260.
    [87] Bhattarai N., Bhattarai S. R., Khil M. S. et al. Aqueous solution properties ofamphiphilic triblock copolymer poly(p-dioxanone-co-L-lactide)-block-poly(ethyleneglycol). European Polymer Journal,2003,39:1603-1608.
    [88] Zou W. W., Liu C. X., Chen Z. J. et al. Preparation and characterization ofcationic PLA-PEG nanoparticles for delivery of plasmid DNA. Nanoscale ResearchLetters,2009,4:982-992.
    [89] Zhou Y. F., Huang W., Liu J. Y. et al. Self-Assembly of hyperbranched polymersand its biomedical applications. Advanced Materials,2010,22:4567-4590.
    [90] Sharma R., Lee J. S., Bettencourt R. C. et al. Effects of the incorporation of ahydrophobic middle block into a PEG-polycation diblock copolymer on thephysicochemical and cell interaction properties of the polymer-DNA complexes.Biomacromolecules,2008,9:3294-3307.
    [91] Miyata K., Christie R. J., Kataoka K. Polymeric micelles for nano-scale drugdelivery. Reactive&Functional Polymers,2011,71:227-234.
    [92] Engelberg I., Kohn J. Physico-mechanical properties of degradable polymersused in medical applications: a comparative study. Biomaterials,1991,12:292-304.
    [93] Wu D. Q., Sun Y. X., Xu X. D. et al. Biodegradable and pH-sensitive hydrogelsfor cell encapsulation and controlled drug release. Biomacromolecules,2008,9:1155-1162.
    [94] Nakayama Y., Okuda S., Yasuda H. et al. Synthesis of multiblockPoly(L-lactide)-co-poly(epsilon-caprolactone) from hydroxy-telechelic prepolymersprepared by using neodymium tetrahydroborate. Reactive&Functional Polymers,2007,67:798-806.
    [95] Gaucher G., Dufresne M. H., Sant V. P. et al. Block copolymer micelles:preparation, characterization and application in drug delivery. Journal of ControlledRelease,2005,109:169-188.
    [96] Kim S., Kim J. H., Jeon O. et al. Engineered polymers for advanced drugdelivery. European Journal of Pharmaceutics and Biopharmaceutics,2009,71:420-430.
    [97] Piao L. H., Dai Z. L., Deng M. X. et al. Synthesis and characterization ofPCL/PEG/PCL triblock copolymers by using calcium catalyst. Polymer,2003,44:2025-2031.
    [98] Mason M. N., Metters A. T., Bowman C. N. et al. Predicting controlled-releasebehavior of degradable PLA-b-PEG-b-PLA hydrogels. Macromolecules,2001,34:4630-4635.
    [99] Anseth K. S., Metters A. T., Bryant S. J. et al. In situ forming degradablenetworks and their application in tissue engineering and drug delivery. Journal ofControlled Release,2002,78:199-209.
    [100] Bahadur K. C. R., Bhattarai S. R., Aryal S. et al. Novel amphiphilic triblockcopolymer based on PPDO, PCL, and PEG: Synthesis, characterization, and aqueousdispersion. Colloids and Surfaces A: Physicochemical and Engineering Aspects,2007,292:69-78.
    [101] Xie Z., Guan H., Chen X. et al. A novel polymer-paclitaxel conjugate based onamphiphilic triblock copolymer. Journal of Controlled Release,2007,117:210-216.
    [102] Kim J. O., Kabanov A. V., Bronich T. K. Polymer micelles with cross-linkedpolyanion core for delivery of a cationic drug doxorubicin. Journal of ControlledRelease,2009,138:197-204.
    [103] McDaniel J. R., Callahan D. J., Chilkoti A. Drug delivery to solid tumors byelastin-like polypeptides. Advanced Drug Delivery Reviews,2010,62:1456-1467.
    [104] Lopez V. C., Raghavan S. L., Snowden M. J. Colloidal microgels as transdermaldelivery systems. Reactive&Functional Polymers,2004,58:175-185.
    [105] Feng Y. K., Guo J. T. Biodegradable polydepsipeptides, International Journal ofMolecular Sciences,2009,10:589-615.
    [106] Feng Y. K., Behl M., Kelch S. et al. Biodegradable multiblock copolymersbased on oligodepsipeptides with shape-memory properties. MacromolecularBioscience,2009,9:45-54.
    [107] Feng Y. K., Klee D., Keul, H. et al. Synthesis and characterization of new ABAtriblock copolymers with poly[3(S)-isobutylmorpholine-2,5-dione] and poly(ethyleneoxide) blocks. Macromolecular Chemistry and Physics.1999,200:2276-2283.
    [108] Zhao Y. L., Li J., Yu H. et al. Synthesis and characterization of a novelpolydepsipeptide contained tri-block copolymer (mPEG-PLLA-PMMD) asself-assembly micelle delivery system for paclitaxel. International Journal ofPharmaceutics,2012,430:282-291.
    [109] Ouchi T., Nozaki T., Okamoto Y. et al. Synthesis and enzymatic hydrolysis ofpolydepsipeptides with functionalized pendant groups. Macromolecular Chemistryand Physics,1996,197:1823-1833.
    [110] Helder J., Kohn F. E., Sato S. et al. Macromol. Rapid Commun.19856:9-14.
    [111] Feng Y. K., Guo J. T. Biodegradable polydepsipeptides. International Journal ofMolecular Sciences,2009,10:589-615.
    [112] Abayasinghe N. K., Perera K. P. U., Thomas C. et al. Amido-modifiedpolylactide for potential tissue engineering applications. Journal of BiomaterialsScience-Polymer Edition,2004,15:595-606.
    [113] Lou X. D., Detrembleur C., Jér me R. Novel aliphatic polyesters based onfunctional cyclic (di)esters. Macromolecular Rapid Communications,2003,24:161-172.
    [114] Deshmukh M., Singh Y., Gunaseelan S. et al. Biodegradable poly(ethyleneglycol) hydrogels based on a self-elimination degradation mechanism. Biomaterials,201031:6675-6684.
    [115] Mallakpour S., Soltanian S., Sabzalian M. R. Studies on synthesis and in vitrobiodegradability of novel optically active nanostructure poly(ester-imide)s containingl-phenylalanine and l-isoleucine linkages. Colloid and Polymer Science,2011,289:93-100.
    [116] Green J. J., Zhou B. Y., Mitalipova M. M. et al. Nanoparticles for gene transferto human embryonic stem cell colonies. Nano Letters,2008,8:3126-3130.
    [117] Chen S. C., Zhou Z. X., Wang Y. Z. et al. A novel biodegradablepoly(p-dioxanone)-grafted poly(vinyl alcohol) copolymer with a controllable in vitrodegradation. Polymer,2006,47:32-36.
    [118] Zheng L., Wang Y. Z., Yang K. K. et al. Effect of PEG on the crystallization ofPPDO/PEG blends. European Polymer Journal,2005,41:1243-1250.
    [119] Kulkarni A., Reiche J., Hartmann J. et al. Selective enzymatic degradation ofpoly(epsilon-caprolactone) containing multiblock copolymers. European Journal ofPharmaceutics and Biopharmaceutics.2008,68:46-56.
    [120] Behl M., Ridder U., Feng Y. K. et al. Shape-memory capability of binarymultiblock copolymer blends with hard and switching domains provided by differentcomponents. Soft Matter,2009,5:676-684.
    [121] Lai Q., Wang Y. Z., Yang K. K. et al. Chain-extension and thermal behaviors ofpoly(p-dioxanone) with toluene-2,4-diisocyanate. Reactive&Functional Polymers,2005,65:309-315.
    [122] Huang F. Y., Wang Y. Z., Wang X. L. et al. Preparation and characterization of anovel biodegradable poly(p-dioxanone)/montmorillonite nanocomposite. Journal ofPolymer Science Part A-Polymer Chemistry,2005,43:2298-2303.
    [123] Bhattarai N., Jiang W. Y., Kim H. Y., et al. Synthesis and hydrolytic degradationof a random copolymer derived from1,4-dioxan-2-one and glycolide. Journal ofPolymer Science Part B-Polymer Physics,2004,42:2558-2566.
    [124] Bezwada R. S., Cooper K. US Patent,5714551,1998.
    [125] Nishida H., Yamashita M., Nagashima M. et al. Equilibrium polymerizationbehavior of1,4-dioxan-2-one in bulk. Macromolecules,2000,33:6982-6986.
    [126] Chen S. C., Zhou Z. X., Wang Y. Z. et al. A novel biodegradablepoly(p-dioxanone)-grafted poly(vinyl alcohol) copolymer with a controllable in vitrodegradation. Polymer,2006,47:32-36.
    [127] Li F., Feng J., Zhou R. X. Synthesis and characterization of novel biodegradablepoly(p-dioxanone-co-ethyl ethylene phosphate)s. Journal of Applied Polymer Science,2006,102:5507-5511.
    [128] Wang H., Dong J. H., Qiu K. Y. et al. Synthesis ofpoly(1,4-dioxan-2-one-co-trimethylene carbonate) for application in drug deliverysystems. Journal of Polymer Science Part A-Polymer Chemistry,1998,36:1301-1307.
    [129] Zhang Y. H., Wang X. L., Wang Y. Z. et al. A novel biodegradable polyesterfrom chain-extension of poly(p-dioxanone) with poly(butylene succinate). PolymerDegradation and Stability,2005,88:294-299.
    [130] Jiang Z. Z., Azim H., Gross R. A. et al. Lipase-catalyzed copolymerization ofomega-pentadecalactone with p-dioxanone and characterization of copolymer thermaland crystalline properties. Biomacromolecules,2007,8:2262-2269.
    [131] Wang X. L., Yang K. K., Wang Y. Z. et al. Crystallization and morphology ofstarch-g-poly(1,4-dioxan-2-one) copolymers. Polymer,2004,45:7961-7968.
    [132] Liu G. Y., Zhai Y. L., Wang X. L. et al. Preparation, characterization, and invitro drug release behavior of biodegradable chitosan-graft-poly(1,4-dioxan-2-one)copolymer. Carbohydrate Polymers,2008,74:862-867.
    [133] Zhu J., Wang W. T., Wang X. L. et al. Green synthesis of a novel biodegradablecopolymer base on cellulose and poly(p-dioxanone) in ionic liquid. CarbohydratePolymers,2009,76:139-144.
    [134] Huang H. X., Yang K. K., Wang Y. Z. et al. Synthesis, characterization, andthermal properties of a novel pentaerythritol-initiated star-shaped poly(p-dioxanone).Journal of Polymer Science Part A-Polymer Chemistry,2006,44:1245-1251.
    [135]Fu F. S., Raymond C.G. US Patent,4916209,1990.
    [136] Feng Y. K., Behl M., Kelch S. et al. Biodegradable multiblock copolymersbased on oligodepsipeptides with shape-memory properties. MacromolecularBioscience,2009,9:45-54.
    [137] Yan J., Ye Z., Chen M. et al. Fine Tuning Micellar Core-Forming Block ofPoly(ethylene glycol)-block-poly(epsilon-caprolactone) Amphiphilic CopolymersBased on Chemical Modification for the Solubilization and Delivery of Doxorubicin.Biomacromolecules,2011,12:2562-2572.
    [138] Zhu Y., Che L., He H. et al. Highly efficient nanomedicines assembled viapolymer-drug multiple interactions: Tissue-selective delivery carriers. Journal ofControlled Release,2011,152:317-324.
    [139] Kim S. H., Tan P. K., Nederberg F. et al. Hydrogen bonding-enhanced micelleassemblies for drug delivery. Biomaterials,2010,31:8063-8071.
    [140] Kataoka K., Matsumotob T., Yokoyamac M. et al. Doxorubicin-loadedpoly(ethylene glycol)-poly(beta-benzyl-l-aspartate) copolymer micelles: theirpharmaceutical characteristics and biological significance. Journal of ControlledRelease,2000,64:143-153.
    [141] Li Y., Gu B. H., Tolley H. D. et al. Preparation of polymeric monoliths bycopolymerization of acrylate monomers with amine functionalities foranion-exchange capillary liquid chromatography of proteins. Journal ofChromatography A,2009,1216:5525-5532.
    [142] Sharma R., Lee J. S., Bettencourt R. C. et al. Effects of the incorporation of ahydrophobic middle block into a PEG-polycation diblock copolymer on thephysicochemical and cell interaction properties of the polymer-DNA complexes.Biomacromolecules,2008,9:3294-3307.
    [143] Luo S. Z., Han M. C., Cao Y. H. et al. Temperature-and pH-responsiveunimolecular micelles with a hydrophobic hyperbranched core. Colloid and PolymerScience,2011,289:1243-1251.
    [144] Zhu C. H., Zheng M., Meng F. H. et al. Reversibly shielded DNA polyplexesbased on bioreducible PDMAEMA-SS-PEG-SS-PDMAEMA triblock copolymersmediate markedly enhanced nonviral gene transfection. Biomacromolecules,2012,13:769-778.
    [145] Bao H. Q., Hu J. H., Gan L. H. et al. Stepped association of comb-like andstimuli-responsive graft chitosan copolymer synthesized using ATRP and active esterconjugation methods. Journal of Polymer Science Part A-Polymer Chemistry,2009,47:6982-6992.
    [146] Meng F. H., Zhong Z. Y., Feijen J. Stimuli-responsive polymersomes forprogrammed drug delivery. Biomacromolecules,2009,10:197-209.
    [147] Park J. H., Kwon S., Lee M. et al. Self-assembled nanoparticles based on glycolchitosan bearing hydrophobic moieties as carriers for doxorubicin: In vivobiodistribution and anti-tumor activity. Biomaterials,2006,27:119-126.
    [148] Wu Z. H., Zeng X. H., Zhang Y. N. et al. Linear-dendritic polymericamphiphiles as carriers of doxorubicin-in vitro evaluation of biocompatibility anddrug delivery. Journal of Polymer Science Part A-Polymer Chemistry,2012,50:217-226.
    [149] Wilhelm M., Zhao C. L., Wang Y. et al.. Macromolecules199124:1033.
    [150] Endres T. K., Beck-Broichsitter M., Samsonova O. et al. Self-assembledbiodegradable amphiphilic PEG-PCL-lPEI triblock copolymers at the borderlinebetween micelles and nanoparticles designed for drug and gene delivery. Biomaterials,2011,32:7721-7731.
    [151] Huang J. H., Zhou Y., Huang K. L. et al. Adsorption behavior, thermodynamics,and mechanism of phenol on polymeric adsorbents with amide group in cyclohexane.Journal of Colloid and Interface Science,2007,316:10-18.
    [152] Zhang S. P., Sun Y. Further studies on the contribution of electrostatic andhydrophobic interactions to protein adsorption on dye-ligand adsorbents.Biotechnology and Bioengineering,2001,75:710-717.
    [153] Wang H. F., Jia H. Z., Cheng S. X. et al. PEG-stabilized micellar system withpositively charged polyester core for fast pH-responsive drug release. PharmaceuticalResearch,2012,29:1582-1594.
    [154] Xue Y. N., Huang Z. Z., Zhang J. T. et al. Synthesis and self-assembly ofamphiphilic poly(acrylic acid-b-DL-lactide) to form micelles for pH-responsive drugdelivery. Polymer,2009,50:3706-3713.
    [155] Kainthan R. K., Mugabe C., Burt H. M. et al. Unimolecular micelles based onhydrophobically derivatized hyperbranched polyglycerols: Ligand binding properties.Biomacromolecules,2008,9:886-895.
    [156] Peng Y. J., Wen C. W., Chiou S. H. et al. Sustained release of ganciclovir andfoscarnet from biodegradable scleral plugs for the treatment of cytomegalovirusretinitis. Biomaterials,2010,31:1773-1779.
    [157] Gong C. Y., Shi S., Wang X. H. et al. Novel composite drug delivery system forhonokiol delivery: self-assembled poly(ethyleneglycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) micelles in thermosensitivepoly(ethylene glycol)-poly(epsilon-caprolactone)-poly(ethylene glycol) hydrogel.Journal of Physical Chemistry B,2009,113:10183-10188.
    [158] Liu G. Y., Zhai Y. L., Wang X. L. et al. Preparation, characterization, and invitro drug release behavior of biodegradable chitosan-graft-poly(1,4-dioxan-2-one)copolymer. Carbohydrate Polymers,2008,74:862-867.
    [159] Nam K., Watanabe J., Ishihara K. Modeling of swelling and drug releasebehavior of spontaneously forming hydrogels composed of phospholipid polymers.International Journal of Pharmaceutics,2004,275:259-269.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700