摘要
聚己内酯类材料由于其良好的生物相容性及长效降解性,在药物控释载体、基因转染等领域具有广泛的应用前景。聚缩水甘油醚是一类具有超支状结构,带有大量可修饰末端基团的高分子聚合材料,具有很好的溶解性和生物相容性。本研究合成了一种新型的超支化聚己内酯/聚缩水甘油醚共聚物(poly(epsilon-caprolactone)-b-hyperbranchedpolyglycidol,PCL-b-HPG)。PCL-b-HPG具有两亲性且带有大量羟基末端基团,能改善聚己内酯的亲水性和可修饰性。将PCL-b-HPG制备成纳米胶束,考察了其细胞毒性和基因转染效果,末端偶联RGD多肽,以期为开发新型靶向药物传递系统奠定基础。
首先以辛酸亚锡(Sn(Oct)_2)为催化剂、月桂醇(1-Dodecanol)为引发剂,将己内酯单体聚合成一定分子量羟端基聚己内酯。随后采用阴离子聚合法,以二氧六环为溶剂,在萘钾为催化剂作用下,使羟端基聚己内酯引发缩水甘油醚聚合,合成了PCL-b-HPG。所得产物结构通过核磁共振氢谱(H~1NMR)、红外光谱(IR)和葡聚糖凝胶色谱(GPC)进行了表征。进一步对PCL-b-HPG嵌段共聚物反应条件进行考察,实验证实反应时间为5h,滴加速度小于1 mL/h时,反应条件最优。
此外采用活性聚合法,以负离子络合型催化剂双金属μ—氧桥烷氧化物([(n-BuO)_2AlO]_2Zn)催化ε—己内酯聚合,得到活性PCL预聚物,进一步引发缩水甘油醚聚合,成功的合成了带有大量端羟基的AB型嵌段共聚物PCL-b-HPG。与阴离子聚合法相比,通过“活”性聚合得到的嵌段共聚物的多分散度Mw/Mn为1.3左右,分散性较低。GPC、~1HNMR、DSC测定结果表明所得共聚物的结构基本符合预定结构。当己内酯和缩水甘油醚单体投料摩尔比为1:2时,反应时间10h,缩水甘油醚单体滴液速度为2 mL/h,达到最适反应条件。
采用界面沉淀法成功制备了PCL-b-HPG纳米胶束。通过TEM、SEM和粒径分析仪观察,所得纳米胶束为球形,形状均匀,粒径为(170±10.0)nm。采用MTT法,检测了PCL-b-HPG纳米胶束的细胞毒性,并制备了载pEGFP-C1基因纳米胶束,所制备的纳米胶束的平均粒径约为225nm,pEGFP-C1质粒的含量约占2%,基因包埋效率在85%以上。凝胶阻滞电泳实验,显示以纳米胶束的形式装载基因,泳道中出现了明显的拖带,表明PCL-b-HPG纳米胶束能有效的包裹质粒DNA分子,体外EA.hy926细胞转染实验证实PCL-b-HPG载基因纳米胶束能够转染质粒DNA,转染效率约在15%。
以N-甘氨酸马来酰亚胺直接偶联法和PCL-b-HPG羧化改性/酰胺键偶联法将RGD4C连接于PCL-b-HPG纳米胶束表面。通过IR、XPS等检测技术证实RGD成功连接于纳米粒表面。表面RGD化的纳米胶束可以识别肿瘤血管内皮上的整合素受体,使之有机会成为新型靶向药物传递系统。
Biodegradable materials based on poly(ε-caprolactone) were widely used for drug delivery and gene transfection due to their good biocompatibility and long-term degradability. Polyglycidol is a soluble and biocompatible polymer which has hyperbranched architecture with numerous hydroxyl end groups.
In present study,a novel di-block copolymer of poly(ε-caprolactone)-b-hyperbranched polyglycidol(PCL-b-HPG) was synthesized.Compared to PCL homopolymer,the PCL-b-HPG has improved solubility and modifiability owing to the introduced hydroxyl end groups.The PCL-b-HPG copolymer was used to prepare nanomicelles with reporter GFP gene and cytotoxicity and gene transfection efficiency of the gene nanomicelle were evaluated.The PCL-b-HPG-based nanomicelles were further chemically coupled with RGD4C peptide,which we thought to lay a preliminary foundation for developing new targeted drug delivery system.
First,a hydroxyl-terminated PCL was prepared by ring-opening polymerization using 1-dodecanol as initiator and stannous octanoate as catalyst.The obtained PCL was treated with naphthalene potassium to get a PCL-based macro-initiator,which was used to initiate glycidol polymerization to form the amphiphilic copolymer of PCL-b-HPG.Chemical structure of the PCL-b-HPG was characterized by ~1H NMR,GPC and IR.Optimal parameters for the copolymerization procedure were established by series of experiments,i.e.1mL/hour of glycidol adding rate and 5 hours of total reaction time.
A novel living copolymerization was designed for better control of the copolymer configuration.The living poly(ε-carprolatone) was synthesized by an ionic-coordination catalyst,named bimetallicμ-oxoalkoxides.The living system of PCL further initiated the polymerization of glycidol to form the block copolymer of PCL-b-HPG.In comparison with anion polymerization,PCL-b-HPG obtained from living copolymerization has lower polydispersity with Mw/Mn of 1.3.Within this system,optimal production conditions were set as follows:reaction time for 10 hours,glycidol adding rate at 2mL/hour and CL/glycidol ratio of 1:2.Chemical Structure of the resultant PCL-b-HPG was characterized by ~1H NMR, GPC,DSC and IR.
Nanomicelles of the amphiphilic poly(epsilon-caprolactone)-b-hyperbranched polyglycidol(PCL-b-HPG) were prepared for further evaluation as targeted drug delivery vehicles.Size and morphology of the nanomicelles were characterized by TEM、SEM and DLS,respectively.The nanomicelles were spherical in uniform shape with diameter ranging from 170±10.0nm.Cytotoxicity of the PCL-b-HPG nanomicelles was evaluated by means of MTT assay.Subsequently,a reportr gene of pEGFP-C1 was loaded into the PCL-b-HPG nanomicelles of 225 nm in size.The loading efficiency is measured over 85%and the ratio of pEGFP-C1 to nanomicelles is about 1:50.In gel electrophoresis,obvious smears appeared when plasmid DNA was packaged into nanomicelles,indicating PCL-b-HPG-based nanomicelles have potential to serve as an efficient gene carrier.The yields of transfection efficiency were found to be 15%when the polyplexes were transfected to EA.hy926.These results demonstrated that the PCL-b-HPG/DNA nanomicelles are effective gene vector in vitro.
RGD4C peptide was conjugated on the surface of PCL-b-HPG nanomicelle by a series of chemical reactions,such as direct coupling using N-glycine maleic anhydride as crosslinker, or modifying the hydroxyl end groups of the PCL-b-HPG molecules with carboxyl groups followed by coupling using acylamide chemical bond.The conjugation of RGD4C was confirmed by IR or XPS spectrum.It was hypothesized that the RGD4C-conjugated PCL-b-HPG nanomicelle be capable of specifically recognizing tumor neovascular endothelium,therefore may offer great opportunities for developing novel tumor-targeting drug delivery system.
引文
[1]Nishikawa M,Huang L.Nonviral vectors in the new millennium:Delivery barriers in gene transfer[J].HUMAN GENE THERAPY,2001,12(8):861-870.
[2]Anderson W F.Human gene therapy[J].NATURE,1998,392(6679):25-30.
[3]Patri A K,Kukowska-Latallo J F,Baker J R.Targeted drug delivery with dendrimers:Comparison of the release kinetics of covalently conjugated drug and non-covalent drug inclusion complex[J].ADVANCED DRUG DELIVERY REVIEWS,2005,57(15):2203-2214.
[4]Lee C C,Mackay J A,Frechet J,et al.Designing dendrimers for biological applications[J].NATURE BIOTECHNOLOGY,2005,23(12):1517-1526.
[5]Voit B I.Hyperbranched polymers:a chance and a challenge[J].COMPTES RENDUS CHIMIE,2003,6(8-10):821-832.
[6]Gao C,Yan D.Hyperbranched polymers:from synthesis to applications[J].PROGRESS IN POLYMER SCIENCE,2004,29(3):183-275.
[7]Yates C R,Hayes W.Synthesis and applications of hyperbranched polymers[J].EUROPEAN POLYMER JOURNAL,2004,40(7):1257-1281.
[8]Morgan J R,Cloninger M J.Heterogeneously functionalized dendrimers[J].CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT,2002,5(6):966-973.
[9]谭惠民.超支化聚合物[M].北京:化学工业出版社,2005.286.
[10]徐祖顺.聚合物纳米粒子[M].北京:化学工业出版社,2006.333.
[11]Kim Y H,Beckerbauer R.ROLE OF END-GROUPS ON THE GLASS-TRANSITION OF HYPERBRANCHED POLYPHENYLENE AND TRIPHENYLBENZENE DERIVATIVES[J].MACROMOLECULES,1994,27(7):1968-1971.
[12]宁萌,黄鹏程.超支化高分子研究进展[J].高分子材料科学与工程,2002(06).
[13]Muzafarov A M,Golly M,Moiler M.DEGRADABLE HYPERBRANCHED POLY(BIS(UNDECENYLOXY)METHYLSILANE)S[J].MACROMOLECULES,1995,28(24):8444-8446.
[14]Williams D F.A MODEL FOR BIOCOMPATIBILITY AND ITS EVALUATION[J].JOURNAL OF BIOMEDICAL ENGINEERING,1989,11(3):185-191.
[15]Duncan R,Izzo L.Dendrimer biocompatibility and toxicity[J].ADVANCED DRUG DELIVERY REVIEWS,2005,57(15):2215-2237.
[16]De Xyloyiannis M P J O L.PEG-dendron architecture influences endocytic capture and intracellular trafficking[J].Proceed.Int'1.Symp.Control.Rel.Bioact.Mater,2003,30:149.
[17]Malik N,Wiwattanapatapee R,Klopsch R,et al.Dendrimers:Relationship between structure and biocompatibility in vitro,and preliminary studies on the biodistribution of I-125-labelled polyamidoamine dendrimers in vivo(vol 65,pg 133,2000)[J].JOURNAL OF CONTROLLED RELEASE,2000,68(2):299-302.
[18]Plank C,Mechtler K,Szoka F C,et al.Activation of the complement system by synthetic DNA complexes:A potential barrier for intravenous gene delivery[J].HUMAN GENE THERAPY,1996,7(12):1437-1446.
[19]Eliyahu H,Servel N,Domb A J,et al.Lipoplex-induced hemagglutination:potential involvement in intravenous gene delivery[J].GENE THERAPY,2002,9(13):850-858.
[20]Yordanov A T,Kobayashi H,English S J,et al.Gadolinium-labeled dendrimers as biometric nanoprobes to detect vascular permeability[J].JOURNAL OF MATERIALS CHEMISTRY,2003,13(7):1523-1525.
[21]Roberts Jc B M Z R.Preliminary biological evaluation ofpolyamidoamine(PAMAM) Starburst dendrimers[J].J Biomed Mater Res.,1996,30(1):53-65.
[22]Dufes C,Uchegbu I F,Schatzlein A G.Dendrimers in gene delivery[J].ADVANCED DRUG DELIVERY REVIEWS,2005,57(15):2177-2202.
[23]Kolhe P,Khandare J,Pillai O,et al.Preparation,cellular transport,and activity of polyamidoamine-based dendritic nanodevices with a high drug payload[J].BIOMATERIALS,2006,27(4):660-669.
[24]Kolhe P,Misra E,Kannan R M,et al.Drug complexation,in vitro release and cellular entry of dendrimers and hyperbranched polymers[J].INTERNATIONAL JOURNAL OF PHARMACEUTICS,2003,259(1-2):143-160.
[25]Zanini D,Roy R.Synthesis of new alpha-thiosialodendrimers and their binding properties to the sialic acid specific lectin from Limax flavus[J].JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,1997,119(9):2088-2095.
[26]Liu H B,Uhrich K.Hyperbranched polymeric micelles:Drug encapsulation,release and polymer degradation.[J].ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY,1997,214:262.
[27]Liu M J,Kono K,Frechet J.Water-soluble dendritic unimolecular micelles:Their potential as drug delivery agents[J].JOURNAL OF CONTROLLED RELEASE,2000,65(1-2):121-131.
[28]Malik N,Evagorou E G,Duncan R.Dendrimer-platinate:a novel approach to cancer chemotherapy[J].ANTI-CANCER DRUGS,1999,10(8):767-776.
[29]Kojima C,Kono K,Maruyama K,et al.Synthesis of polyamidoamine dendrimers having poly(ethylene glycol)grafts and their ability to encapsulate anticancer drugs[J].BIOCONJUGATE CHEMISTRY,2000,11(6):910-917.
[30]Bhadra D,Bhadra S,Jain S,et al.A PEGylated dendritic nanoparticulate carrier of fluorouracil[J].INTERNATIONAL JOURNAL OF PHARMACEUTICS,2003,257(1-2):111-124.
[31]De Jesus O,Ihre H R,Gagne L,et al.Polyester dendritic systems for drug delivery applications:In vitro and in vivo evaluation[J].BIOCONJUGATE CHEMISTRY,2002,13(3):453-461.
[32]Kannan S,Kolhe P,Raykova V,et al.Dynamics of cellular entry and drug delivery by dendritic polymers into human lung epithelial carcinoma cells[J].JOURNAL OF BIOMATERIALS SCIENCE-POLYMER EDITION,2004,15(3):311-330.
[33]张倩瑶,王向涛,Qianyao z,et al.中国医药技术经济与管理,2008,2(10).
[34]Okuda T,Kawakami S,Akimoto N,et al.PEGylated lysine dendrimers for tumor-selective targeting after intravenous injection in tumor-bearing mice| J].JOURNAL OF CONTROLLED RELEASE,2006,116(3):330-336.
[35]Quintana A,Raczka E,Piehler L,et al.Design and function of a dendrimer-based therapeutic nanodevice targeted to tumor cells through the folate receptor[J].PHARMACEUTICAL RESEARCH,2002,19(9):1310-1316.
[36]Wiwattanapatapee R,Lomlim L,Saramunee K.Dendrimers conjugates for colonic delivery of 5-aminosalicylic acid[J].JOURNAL OF CONTROLLED RELEASE,2003,88(1):1-9.
[37]Witvrouw M,Fikkert V,Pluymers W,et al.Polyanionic(i.e.,polysulfonate)dendrimers can inhibit the replication of human immunodeficiency virus by interfering with both virus adsorption and later steps(Reverse transcriptase/integrase)in the virus replicative cycle[J].MOLECULAR PHARMACOLOGY,2000,58(5):1100-1108.
[38]Haensler J,Szoka F C.POLYAMIDOAMINE CASCADE POLYMERS MEDIATE EFFICIENT TRANSFECTION OF CELLS IN CULTURE[J].BIOCONJUGATE CHEMISTRY,1993,4(5):372-379.
[39]Bielinska A U,Kukowskalatallo J F,Baker J R.The interaction of plasmid DNA with polyamidoamine dendrimers:mechanism of complex formation and analysis of alterations induced in nuclease sensitivity and transcriptional activity of the complexed DNA[J].BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION,1997,1353(2):180-190.
[40]Arima H,Kihara F,Hirayama F,et al.Enhancement of gene expression by polyamidoamine dendrimer conjugates with alpha-,beta-,and gamma-cyclodextrins[J].BIOCONJUGATE CHEMISTRY,2001,12(4):476-484.
[41]Tang M X,Szoka F C.The influence of polymer structure on the interactions of cationic polymers with DNA and morphology of the resulting complexes[J].GENE THERAPY,1997,4(8):823-832.
[42]Zinselmeyer B H,Mackay S P,Schatzlein A G,et al.The lower-generation polypropylenimine dendrimers are effective gene-transfer agents[J].PHARMACEUTICAL RESEARCH,2002,19(7):960-967.
[43]Gebhart C L,Kabanov A V.Evaluation of polyplexes as gene transfer agents[J].JOURNAL OF CONTROLLED RELEASE,2001,73(2-3):401-416.
[44]Al-Jamal K T,Ramaswamy C,Florence A T.Supramolecular structures from dendrons and dendrimers[J].ADVANCED DRUG DELIVERY REVIEWS,2005,57(15):2238-2270.
[45]Jorg Dennig E D.Gene transfer into eukaryotic cells using activated polyamidoamine dendrimers[J].Reviews in Molecular Biotechnology,2002,90(3-4):339-347.
[46]Yoo H,Juliano R L.Enhanced delivery of antisense oligonucleotides with fluorophore-conjugated PAMAM dendrimers[J].NUCLEIC ACIDS RESEARCH,2000,28(21):4225-4231.
[47]Boas U,Heegaard P.Dendrimers in drug research[J].CHEMICAL SOCIETY REVIEWS,2004,33(1):43-63.
[48]Nishiyama N,Stapert H R,Zhang G D,et al.Light-harvesting ionic dendrimer porphyrins as new photosensitizers for photodynamic therapy[J].BIOCONJUGATE CHEMISTRY,2003,14(1):58-66.
[49]Zhang G D,Harada A,Nishiyama N,et al.Polyion complex micelles entrapping cationic dendrimer porphyrin:effective photosensitizer for photodynamic therapy of cancer[J].JOURNAL OF CONTROLLED RELEASE,2003,93(2):141-150.
[50]Battah S H,Chee C E,Nakanishi H,et al.Synthesis and biological studies of 5-aminolevulinic acid-containing dendrimers for photodynamic therapy[J].BIOCONJUGATE CHEMISTRY,2001,12(6):980-988.
[51]Paul A,Hackbarth S,Molich A,et al.Comparative study of the photosensitization of Jurkat cells in vitro by pheophorbide-a and a pheophorbide-a diaminobutane poly-propylene-imine dendrimer complex[J].LASER PHYSICS,2003,13(1):22-29.
[52]Fischer M,Vogtle F.Dendrimers:From design to application-A progress report[J].ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,1999,38(7):885-905.
[53]Jevprasesphant R,Penny J,Jalal R,et al.The influence of surface modification on the cytotoxicity of PAMAM dendrimers[J].INTERNATIONAL JOURNAL OF PHARMACEUTICS,2003,252(1-2):263-266.
[54]Kobayashi H,Kawamoto S,Jo S K,et al.Macromolecular MRI contrast agents with small dendrimers:Pharmacokinetic differences between sizes and cores[J].BIOCONJUGATE CHEMISTRY,2003,14(2):388-394.
[55]Hecht S,Frechet J.Dendritic encapsulation of function:Applying nature's site isolation principle from biomimetics to materials science[J].ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2001,40(1):74-91.
[56]Jiang D L,Aida T.A dendritic iron porphyrin as a novel haemoprotein mimic:Effects of the dendrimer cage on dioxygen-binding activity[J].CHEMICAL COMMUNICATIONS,1996(13):1523-1524.
[57]Dandliker P J,Diederich F,Zingg A,et al.Dendrimers with porphyrin cores:Synthetic models for globular heme proteins[J].HELVETICA CHIMICA ACTA,1997,80(6):1773-1801.
[58]Weyermann P,Gisselbrecht J P,Boudon C,et al.Dendritic iron porphyrins with tethered axial ligands:New model compounds for cytochromes[J].ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,1999,38(21):3215-3219.
[59]Hudde T,Rayner S A,Comer R M,et al.Activated polyamidoamine dendrimers,a non-viral vector for gene transfer to the corneal endothelium[J].GENE THERAPY,1999,6(5):939-943.
[60]Singh P.Terminal groups in starburst dendrimers:Activation and reactions with proteins[J].BIOCONJUGATE CHEMISTRY,1998,9(1):54-63.
[61]Tomalia D A.Birth of a new macromolecular architecture:Dendrimers as quantized building blocks for nanoscale synthetic organic chemistry[J].ALDRICHIMICA ACTA,2004,37(2):39-57.
[62]Watkins D M,Sayedsweet Y,Klimash J W,et al.Dendrimers with hydrophobic cores and the formation of supramolecular dendrimer-surfactant assemblies[J].LANGMUIR,1997,13(12):3136-3141.
[63]Cosulich M E,Russo S,Pasquale S,et al.Performance evaluation of hyperbranched aramids as potential supports for protein immobilization[J].POLYMER,2000,41(13):4951-4956.
[64]Sunder A,Hanselmann R,Frey H,et al.Controlled synthesis of hyperbranched polyglycerols by ring-opening multibranching polymerization[J].MACROMOLECULES,1999,32(13):4240-4246.
[65]Kainthan R K,Hester S R,Levin E,et al.In vitro biological evaluation of high molecular weight hyperbranched polyglycerols[J].BIOMATERIALS,2007,28(31):4581-4590.
[66]Hanselmann R,Holter D,Frey H.Hyperbranched polymers prepared via the core-dilution slow addition technique:Computer simulation of molecular weight distribution and degree of branching[J].MACROMOLECULES,1998,31(12):3790-3801.
[67]Kautz H,Sunder A,Frey H.Control of the molecular weight of hyperbranched polyglycerols[J].MACROMOLECULAR SYMPOSIA,2001,163:67-73.
[68]Sunder A,Frey H,Mulhaupt R.Hyperbranched polyglycerols by ring-opening multibranching polymerization[J].MACROMOLECULAR SYMPOSIA,2000,153:187-196.
[69]Holger Frey R H.Dendritic polyglycerol:a new versatile biocompatible material[J].Reviews in Molecular Biotechnology,2002,90(3-4):257-267.
[70]Wilson R,Van Schie B J,Howes D.Overview of the preparation,use and biological studies on polyglycerol polyricinoleate(PGPR)[J].FOOD AND CHEMICAL TOXICOLOGY,1998,36(9-10):711-718.
[71]Sunder A,Mulhaupt R,Haag R,et al.Chiral hyperbranched dendron analogues[J]. MACROMOLECULES,2000,33(2):253-254.
[72]Kolhe P,Khandare J,Pillai O,et al.Hyperbranched polymer-drug conjugates with high drug payload for enhanced cellular delivery[J].PHARMACEUTICAL RESEARCH,2004,21(12):2185-2195.
[73]Kumar K R,Brooks D E.Comparison of hyperbranched and linear polyglycidol unimolecular reverse micelles as nanoreactors and nanocapsules[J].MACROMOLECULAR RAPID COMMUNICATIONS,2005,26(3):155-159.
[74]Sunder A,Kramer M,Hanselmann R,et al.Molecular nanocapsules based on amphiphilic hyperbranched polyglycerols[J].ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,1999,38(23):3552-3555.
[75]Mecking S,Thomann R,Frey H,et al.Preparation of catalytically active palladium nanoclusters in compartments of amphiphilic hyperbranched polyglycerols[J].MACROMOLECULES,2000,33(11):3958-3960.
[76]於秋霞,朱光明,梁国正.聚己内酯的合成、性能和应用研究[J].高分子材料科学与工程,2004,20(5):37-41.
[77]Rohner,D R,Hutmacher,et al.Individuell mit CAD-CAM-Technik hergestellte,bioresorbierbare dreidimensionale Polycaprolaktonger(u|¨)ste zur experimentellen Rekonstruktion von kraniofazialen Defekten beim Schwein[J].Mund-,Kiefer-und Gesichtschirurgie,2002,6(3):162-167.
[78]王永亮,易国斌,康正,等聚己内酯的合成与应用研究进展[J].化学与生物工程,2006(03).
[79]艾合麦提玉素甫,王振斌,朱良.可生物降解材料聚己内酯在医学上的应用进展[J].国外医学.生物医学工程分册,2005(01).
[80]陈建海,黄春霞,陈志良.聚己内酯材料的生物相容性与毒理学研究[J].生物医学工程学杂志,2000(04).
[81]宁漱岩,刘建国,徐莘香,等人工合成骨科生物降解可吸收材料的细胞毒理学实验研究[J].白求恩医科大学学报,2000(05).
[82]Sinha V R,Bansal K,Kaushik R,et al.Poly-epsilon-caprolactone microspheres and nanospheres:an overview[J].INTERNATIONAL JOURNAL OF PHARMACEUTICS,2004,278(1):1-23.
[83]宋存先,王彭廷,孙洪范,等聚己内酯在体内的降解、吸收和排泄[J].生物医学工程学杂志,2000(01).
[84]於秋霞,朱光明,梁国正,et al.聚ε-己内酯的合成、性能及应用进展[J].高分子材料科学与工程,2004(05).
[85]谢长琼,周元林,马佳俊.聚己内酯改性研究进展[J].塑料科技,2009,37(4).
[86]Averous L,Fringant C.Association between plasticized starch and polyesters:Processing and performances of injected biodegradable systems[J].POLYMER ENGINEERING AND SCIENCE,2001,41(5):727-734.
[87]Averous L,Moro L,Dole P,et al.Properties of thermoplastic blends:starch-polycaprolactone[J].POLYMER,2000,41(11):4157-4167.
[88]苟马玲,张阳德,王辉,等一种聚己内酯-聚乙二醇-聚己内酯磁性共聚物微球的制备[J].高分子材料科学与工程,2007,23(4).
[1]Sun H F,Mei L,Song C X,et al.The in vivo degradation,absorption and excretion of PCL-based implant[J].BIOMATERIALS,2006,27(9):1735-1740.
[2]Sunder A,Hanselmann R,Frey H,et al.Controlled synthesis of hyperbranched polyglycerols by ring-opening multibranching polymerization[J].MACROMOLECULES,1999,32(13):4240-4246.
[3]Kainthan R K,Janzen J,Levin E,et al.Biocompatibility testing of branched and linear polyglycidol[J].BIOMACROMOLECULES,2006,7(3):703-709.
[4]Oosterom G E,Reek J,Kamer P,et al.Transition metal catalysis using functionalized dendrimers[J].ANGEWANDTE CHEMIE-INTERNATIONAL EDITION,2001,40(10):1828-1849.
[5]Frechet J.Dendritic macromolecules at the interface of nanoscience and nanotechnology[J].MACROMOLECULAR SYMPOSIA,2003,201:11-22.
[6]Holger Frey R H.Dendritic polyglycerol:a new versatile biocompatible material[J].Reviews in Molecular Biotechnology,2002,90(3-4):257-267.
[7]G P C.Biodegradable polymers as drug deliver systems.[M].New York:Marcel Dekker,Inc.,1991.71-82.
[8]Halabalova W,Simek L,Dostal J,et al.Note on the relation betweeen the parameters of the Mark-Houwink-Kuhn-Sakurada equation[J].INTERNATIONAL JOURNAL OF POLYMER ANALYSIS AND CHARACTERIZATION,2004,9(1-3):65-75.
[9]Du Xu Ning(许宁)W R F.端基为巯基的聚己内酯的合成[J].Chem.J.Chinese Universities(高等学校化学学报),2007,28(9):1-791.
[10]Kainthan R K,Muliawan E B,Hatzikiriakos S G,et al.Synthesis,characterization,and viscoelastic properties of high molecular weight hyperbranched polyglycerols[J].MACROMOLECULES,2006,39(22):7708-7717.
[1]T.ouhadi C S P T.Makromol.Chem.suppl.1,1975:191-201.
[2]M.osgan P T.J.Polym.Sci.B5,1967:789.
[3]M.osgan P T.J.Polym.Sci.B8,1970:319.
[4]A Hamitou P T.Macromolecules,1973,6(4):651.
[5]A Hamitou T H P T.Soluble bimetallic μ-Oxoalkoxides.Ⅸ.ε-Caprolactone and β-Propiolactone Block Copolymerization[J].Journal of polymer science:polymer Chemistry Edition,1977,15:1035-1041.
[6]Cx.song W C X F.Synthesis and Ebaluation of Biodegradable Block Copolymers of ε-caprolactone and DL-lactide[J].Journal of polymer science:polymer letters edition,1983,21:593-600.
[7]J.henschen P T.Fr 2383208[P].
[8]Osgan M.US.3472445[P].
[9]A.hamitou T O R J.Soluble bimetallic μ-Oxoalkoxides.Ⅶ.Characteristics and Mechanism of Ring-Opening Polymerization of Lactones[J].Journal of Polymer Science:polymer chemistry Edition,1977,15(4):865-873.
[10]Cox E F.U.S.3021,313[P].
[11]Holger Frey R H.Dendritic polyglycerol:a new versatile biocompatible material[J].Reviews in Molecular Biotechnology,2002,90(3-4):257-267.
[1]Af H.Integrin and health[J].Sci Am,1997,276(5):68.
[2]Tremble P D C W.Components of the nuclear signaling cascade that regulates collagenase gene expression in response to integrin-derived signals.[J].J Cell Biol,1995,129(6):1701-1720.
[3]胡宜,王静舒,贾心善.整合素研究的最新进展[J].日本医学介绍,2002,23(4):184-186.
[4]刘俭,郭顺星唐.RGD肽与肿瘤治疗研究进展[J].6,2003,30(3):197.
[5]Zhang J G,Krajden O B,Kainthan R K,et al.Conjugation to hyperbranched polyglycerols improves RGD-mediated inhibition ofplatelet function in vitro[J].BIOCONJUGATE CHEMISTRY,2008,19(6):1241-1247.
[6]Kai Temming R M S G.RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature[J].Drug Resistance Updates,2005,8:381-402.
[7]Koivunen E W B R.Phage libraries displaying cyclic peptides with different ring sizes:ligand specificities of the RGD-directed integfins.[J].Bio-Technology,1995,13:265-270.
[8]Wang D A.Engineering blood-contact hiomaterials by "H-bond grafting" surface modification[J]. FUNCTIONAL MATERIALS AND BIOMATERIALS,2007,209:179-227.
[9]Pourcelle V,Devouge S,Garinot M,et al.PCL-PEG-Based nanoparticles grafted with GRGDS peptide:Preparation and surface analysis by XPS[J].BIOMACROMOLECULES,2007,8(12):3977-3983.