聚羟基脂肪酸酯纳米颗粒作为药物缓释载体的应用
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
在本论文中,PHB、PHBHHx和PLA分别被制作成平均粒径为160nm、250nm和150nm的微小颗粒。一种脂溶性荧光染料罗丹明B(RBITC)被包裹到纳米颗粒中,作为检测胞吞效果及缓释过程的标记。实验中的三种材料所制备的纳米颗粒均能高效的包裹RBITC,装载效率高达75%。装载有RBITC荧光染料的纳米颗粒被原代巨噬细胞胞吞后,检测结果显示,PHB和PHBHHx纳米颗粒中的RBTIC在胞内的缓释可以持续至少20天,而PLA纳米颗粒中的RBITC在第15天就基本已经释放出来,不被材料包裹的RBITC溶液在巨噬细胞中不到7天就已经释放完全。缓释的速度不受载体材料和颗粒大小的差异影响。本研究首次证明PHB和PHBHHx能有效的作为药物载体应用于药物缓释。
In this study, Polyhydroxybutyrate (PHB), copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx), and polylactic acid (PLA) were prepared into nanoparticles with average sizes of 160, 250 and 150 nm, respectively. A lipid soluble colorant rhodamine B isothiocyanate (RBITC) was employed to study drug release behaviors from these nanoparticles. A high RBITC drug loading efficiency of over 75% was achieved with all PHA nanoparticles prepared. Macrophage endocytosis led to an intracellular RBITC drug sustained release over a period of at least 20 days for PHB and PHBHHx nanoparticles, while PLA nanoparticles and free drug lasted only 15 days and a week, respectively. Polymer properties and particle sizes showed little effect on drug release behavior. This study showed for the first time that PHB and PHBHHx can be used effectively to achieve intracellular drug control releases.
引文
[1] Lisa Brannon-Peppas. Polymers in Controlled Drug Delivery. Medical Plastics and Biomaterials Magazine. MPB 1997; 34.
    [2] Lavigne MD, Górecki DC. Emerging vectors and targeting methods for nonviral gene therapy. Expert Opin.Emerging Drugs 2006; 11: 541-57.
    [3] Eliyahu H, Barenholz Y, Domb AJ. Polymers for DNA Delivery. Molecules 2005; 10: 34-64.
    [4] Jeong B, Bae YH, Lee DS, Kim SW. Biodegradable block copolymers as injectable drug-delivery systems. Nature 1997; 388: 860-2.
    [5] Redell MS. Tweardy DJ. Targeting transcnption factors in cancer:Challenges and evolving strategies. Drug Discovery Today:Technologies 2006; 3: 261-7.
    [6] P. R. Lockman; R. J. Mumper; M. A. Khan; D. D. Allen. Nanoparticle technology for drug delivery acrossthe bleed-brain barrier.Drug Development and Industrial Pharmacy 2002; 28: 1-13.
    [7] R. Langer, Tirrell DA. Designing materials for biology and medicine. Nature 2004; 428: 487-92.
    [8] R. Langer, Drug delivery and targeting. Nature 1998; 392: 5-10.
    [9] Hans ML. Lowman AM. Biodegradable nanoparticles for drug delivery and targeting. Current Opinion in Solid State and Materials Science 2002; 6: 319-27.
    [10] Liu J, Meisner D, Kwong E. A novel trans-lymphatic drug delivery system:Implantable gelatin sponge impregnated with PLGA-paclitaxel microspheres.Biomaterials 2007; 28: 3236-44.
    [11] WehreI P,Magenheim B, Benita S.Influence of process parameters on the PLA nanopartical size distribution,evaluated by means of factoda design.Eur J Pharm Biopharm 1995; 41: 1-19.
    [12] Wei Lu, Yu-Zhen Tan, Kai-Li Hu, Xin-Guo Jiang. Cationic albumin conjugated pegylated nanoparticle with its transcytosis ability and little toxicity against blood-brain barrier. International Journal of Pharmaceutics 2005; 295: 247-60.
    [13] Maciejowska J , Kasperczyk J , Dobrzyski P . The Influence of chain microstructure on hydrolytic degradation of glycolide/lactide copolymers used in drug delivery systems. J Control Release 2006; 116: e6-e8.
    [14] Tack F,Bakker A,Maes S,et a1.Dendrimeric poly(propylene-imines as effective delivery agents for DNAzymes:Dendrimer synthesis,stability and oligonucleotide complexation.J Control Release 2006; 116: e24-e26.
    [15] Mizushima Y, Ikorea T, Tanaka J. Injectable porous hydroxyapatite microparticles as a new carrier for protein and lipophilic drugs.J Control Release 2006; 110: 260-5.
    [16] Janes KA, Fresneau MP, Marazuela A, el a1. Chitosan nanoparticles as delivery systems for doxorubicin. J Control Release 2001; 73: 255-67.
    [17] Sunderland CJ, Steiert M, Talmadge JE, et a1. Targeted nanoparticles for detecting and treating cancer. Drug Dev Res 2006; 67: 70-93.
    [18] Cao WJ, Cheng J, Wang CG. Novel materials as vehicles for target drug delivery system. Journa of Cinical Rehabitative Tissue Engineering Research 2007; 22: 4380-3.
    [19] Anderson AJ, Dawes EA. Occurrence, metabolism, metabolic role, and industrial use of bacterial polyhydroxyalkanoates. Microbiol Rev 1990; 54: 450-72.
    [20] Madison LL, Huisman GW. Metabolic engineering of poly (3-hydroxyalkanoates): from DNA to plastic. Microbiol Mol Biol Rev 1999; 63: 21-53.
    [21] Dawes EA, Senior PJ. The role and regulation of energy reserve polymers in microorganisms. Adv Microb Physiol 1973; 10: 135-266.
    [22] Jendrossek D. Microbial degradation of polyesters. Adv Biochem Eng Biotechnol 2001; 71: 293-325.
    [23] Steinbüchel A, Valentin HE. Diversity of bacterial polyhydroxyalkanoic acids. FEMS Microbiol Lett 1995; 128: 219-28.
    [24] Lee SY, Chang HN. Production of poly-(hydroxyalkanoic acid). Adv. Biochem. Eng. Biotechnol. 1995; 52: 27-58.
    [25] Shimamura E, Kasuya K, Kobayashi G, Shiotani T, Shima Y, Doi Y. Physical properties and biodegradability of microbial poly(3-hydroxybutyrate-co-3-hydroxyhexanoate). Macromolecules 1994; 27: 878-80.
    [26] Doi Y, Kitamura S, Abe H. Microbial synthesis and characterization of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate). Macromolecules 1995; 28: 4822-8.
    [27] Liebergesell M, Mayer F, Steinbüchel A. Analysis of polyhydroxyalkanoic acid-biosynthesis genes of anoxygenic phototrophic bacteria reveals synthesis of a polyester exhibiting an unusual composition. Appl. Microbiol. Biotechnol. 1993; 40: 292-300.
    [28] Lee SH, Oh DH, Ahn WS, Lee Y, Choi J, Lee SY. Production of poly (3-hydroxybutyrate-co-3-hydroxyhexanaote) by high-cell density cultivation of Aeromonas hydrophila. Biotechnol. Bioeng. 2000; 67: 240-4.
    [29] Chen GQ, Zhang G, Park SJ, Lee SY. Industrial scale production of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate). Appl. Microbiol. Biotechnol. 2001; 57: 50-5.
    [30] Abe H, Doi Y, Fukushima T, Eya H. Biosynthesis from gluconate of a random copolyester consisting of 3-hydroxybutyrate and medium-chain-length 3-hydroxyalkanoates by Pseudomonas sp. 61-3. Int. J. Biol. Macromol. 1994; 16: 115-9.
    [31] Kato M, Bao HJ, Kang CK, Fukui T, Doi Y. Production of a novel copolyester of 3-hydroxybutyric acid and medium-chain-length 3-hydroxyalkanoic acids by Pseudomonas sp. 61-3. Appl. Microbiol. Biotechnol. 1996; 45: 363-70.
    [32] Matsusaki H, Manji S, Taguchi K, Kato M, Fukui T, Doi Y. Cloning and molecular analysis of the poly (3-hydroxybutyrate) and poly (3-hydroxybutyrate-co-3-hydroxyalkanoate) biosynthesis genes in Pseudomonas sp. strain 61-3. J. Bacterial 1998; 180: 6459-67.
    [33] Matsusaki H, Abe H, Doi Y. Biosynthesis and properties of poly (3-hydroxybutyrate -co-3-hydroxyalkanoates) by recombinant strains of Pseudomonas sp. 61-3. Biomacromolecules 2000; 1: 17-22.
    [34] Rehm BHA, Steinbüchel A. Biochemical and genetic analysis of PHA synthases and other proteins required for PHA synthesis. Int J Biol Macromol 1999; 25: 3-19.
    [35] Brandl H, Gross R A, Lenz R W, et al. Plastics form bacteria and for bacteria: poly (β-hydroxyalkanoates) as natural, biocompatible, and biodegradable polyesters. Advances in Biochemical Engineering/Biotechnology 1990; 41: 77-93.
    [36] Maehara A, Doi Y, Nishiyama T, Takagi Y, Ueda S, Nakano H, Yamane T. PhaR, a protein of unknown function conserved among short-chain-length polyhydroxyalkanoic acids producing bacteria, is a DNA-binding protein and represses Paracoccus denitrificans phaP expression in vitro. FEMS Microbiol. Lett. 2001; 200: 9-15.
    [37] Sudesh K, Abe H, Doi Y. Synthesis, structure and properties of polyhydroxyalkanoates: biological polyesters. Prog. Polym. Sci. 2000; 25: 1503-55.
    [38] Griebel R, Smith Z, Merrick JM. Metabolism of poly-b-hydroxybutyrate. I. Purification, composition and properties of native poly-b-hydroxybutyrate granules from Bacillus megaterium. Biochemistry 1968; 7: 3676-81.
    [39] Steinbüchel A, Aerts K, Babel W, F?llner C, Liebergesell M, Madkour MH, Mayer F, Pieper-Fürst U, Pries A, Valentin HE, Wieczorek R. Considerations on the structure and biochemistry of bacterial polyhydroxyalkanoic acid inclusions. Can J Microbiol (Suppl) 1995; 41: 94-105.
    [40] Yong-Chao Yao, Xiao-Yong Zhan, Jing Zhang, Xiang-Hui Zou, Zhi-Hui Wang, Yu-Cui Xiong, Jiong Chen, Guo-Qiang Chen. A specific drug targeting system based on polyhydroxyalkanoate granule binding protein PhaP fused with targeted cell ligands. Biomaterials 29 (2008) 4823–30.
    [41] Peoples OP, Sinskey AJ. Poly-β-hydroxybutyrate biosynthesis in Alcaligenes eutrophus H16. Identification and characterization of the PHB polymerase gene (phbC). J. Biol. Chem., 1989; 264: 15298-303.
    [42] Slater SC, Voigt WH, Dennis DE. Cloning and expression in Escherichia coli of the Alcaligenes eutrophus H16 poly-β-hydroxybutyrate biosynthetic pathway. J. Bacterial. 1988; 170: 4431-6.
    [43] Schubert P, Steinbüchel A, Schlegel HG. Cloning of the Alcaligenes eutrophus genes for the synthesis of poly-β-hydroxybutyrate (PHB) and synthesis of PHB in Escherichia coli. J. Bacterial. 1988; 173: 5837-47.
    [44] Rehm BHA, Polyester synthases: natural catalysts for plastics. Biochem. J. 2003; 376: 15–33.
    [45] Rehm BHA, Steinbüchel A. PHA synthases: the key enzymes of PHA synthesis, in: Biopolymers, Vol3a (Doi Y, Steinbüchel A, Eds). Wiley-VCH, Weinheim, Germany, 2000; 173-215.
    [46] Zhang G, Hang XM, Green P, Chen GQ. PCR cloning of type II polyhydroxyalkanoate biosynthesis genes from two pseudomonads strains. FEMS Microbiol. Lett. 2001; 198: 165-170.
    [47] Hang XM, Zhang G, Wang GL, Chen GQ. PCR cloning of polyhydroxyalkanoate biosynthesis genes from Burkholderia caryophylli and their functional expression in recombinant Escherichia coli. FEMS Microbiol. Lett. 2002; 210: 49-54.
    [48] Peters, V., B. H. A. Rehm. In vivo enzyme immobilization by use of engineered polyhydroxyalkanoate synthase. Appl. Environ. Microbiol. 2006; 72: 1777–83.
    [49] Peters, V., B. H. A. Rehm. In vivo monitoring of PHA granule formation using GFP-labeled PHA synthases. FEMS Microbiol. Lett. 2005; 248: 93–100.
    [50] Lundgren DG, Pfister RM, Merrick JM. Structure of poly (β-hydroxybutyric acid) granules. J. Gen. Microbiol. 1964; 34: 441-6.
    [51] Pieper-Fürst U, Madkour MH, Mayer F, et al. Purification and characterization of a 14-kilodalton protein that is bound to the surface of polyhydroxyalkanoic acid granules in Rhodococcus rubber. J. Bacterial. 1994; 176: 4328-37
    [52] Pieper-Fürst U, Madkour MH, Mayer F, et al. Identification of the region of a 14-kilodalton protein of Rhodococcus rubber that is responsible for the binding of this phasin to polyhydroxyalkanoic acid granule. J. Bacterial. 1995; 177: 2513-23.
    [53] Wieczorek R, Pries A, Steinbüchel A. Analysis of a 24-kilodalton protein associated with the polyhydroxyalkanoic acid granules in Alcaligenes eutrophus. J. Bacterial. 1995; 177: 2425-35.
    [54] Maehara A, Ueda S, Nakano H, et al. Analyses of a polyhydroxyalkanoic acid granule-associated 16-kilodalton protein and its putative regulator in the pha locus of Paracoccus denitrificans. J. Bacterial. 1999; 181: 2914-21.
    [55] Jurasek L, Marchessault RH. The role of phasins in the morphogenesis of poly (3-hydroxybutyrate) granules. Biomacromolecules 2002; 3: 256-61.
    [56] Hanley SZ, Pappin DJC, Rahman D, et al. Re-evaluation of the primary structure of Ralstonia eutropha phasin and implications for polyhydroxyalkanoic acid granule binding. FEBS Lett. 1999; 447: 99-105.
    [57] McCool GJ, Cannon MC. Polyhydroxyalkanoate inclusion body-associated proteins and coding region in Bacillus megaterium. J. Bacterial. 1999; 181: 585-92.
    [58] Stuart ES, Tehrani A, Valentin HE, et al. Protein organization on the PHA inclusion cytoplasmic boundary. J. Biotechnol 1998; 64: 137-44.
    [59] Fukui T, Kichise T, Lwata T, et al. Characterization of 13 kDa granule-associated protein in Aeromonas caviae and biosynthesis of polyhydroxyalkanoates with altered molar composition by recombinant bacteria. Biomacromolecules 2001; 2: 148-53.
    [60] Tian SJ, Lai WJ, Zheng Z, et al. Effect of over-expression of phasin gene from Aeromonas hydrophila on biosynthesis of copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate. FEMS Microbiol. Lett. 2005; 244: 19-25.
    [61] York GM, Junker BH, Stubbe J, et al. Accumulation of the PhaP phasin of Ralstonia eutropha is dependent on production of polyhydroxybutyrate in cells. J. Bacteriol. 2001; 183: 4217-26.
    [62] P?tter M, Madkour MH, Mayer F, et al. Regulation of phasin expression and polyhydroxyalkanoate (PHA) granule formation in Ralstonia eutropha H16. Microbiology 2002; 148: 2413-26.
    [63] York GM, Stubbe J, Sinskey AJ. The Ralstonia eutropha PhaR protein couples synthesis of the PhaP phasin to the presence of polyhydroxybutyrate in cells and promotes polyhydroxybutyrate production. J. Bacteriol. 2002; 184: 59-66.
    [64] Maehara A, Doi Y, Nishiyama T, et al. PhaR, a protein of unknown function conserved among short-chain-length polyhydroxyalkanoic acids producing bacteria, is a DNA-binding protein and represses Paracoccus denitrificans phaP expression in vitro. FEMS Microbiol. Lett. 2001; 200: 9-15.
    [65] Yamada M, Wakuda A, Taguchi S. Morphological change in cellular granule formation of poly [(R)-3-hydroxybutyrate] caused by DNA-binding-related mutations of an autoregulated repressor PhaR. Biosci Biotechnol Biochem. 2007; 71: 1572-6.
    [66] P?tter M, Müller H, Steinbüchel A. Influence of homologous phasins (PhaP) on PHA accumulation and regulation of their expression by the transcriptional repressor PhaR in Ralstonia eutropha H16. 2005; 151: 825-33.
    [67] Seo MC, Shin HD, Lee YH. Transcription level of granule-associated phaP and phaR genes and granular morphogenesis of poly-beta-hydroxyalkanoate granules in Ralstonia eutropha. Biotechnol Lett. 2004; 26: 617-22.
    [68] Yamada M, Yamashita K, Wakuda A, Ichimura K, Maehara A, Maeda M, Taguchi S. Autoregulator protein PhaR for biosynthesis of polyhydroxybutyrate [P(3HB)] possibly has two separate domains that bind to the target DNA and P(3HB): Functional mapping of amino acid residues responsible for DNA binding. J Bacteriol. 2007; 189: 1118-27.
    [69] Maehara A, Taguchi S, Nishiyama T, Yamane T, Doi Y. A repressor protein, PhaR, regulates polyhydroxyalkanoate (PHA) synthesis via its direct interaction with PHA. J Bacteriol. 2002; 184: 3992-4002.
    [70] Yamashita K, Yamada M, Numata K, and Taguchi S, Nonspecific Hydrophobic Interactions of a Repressor Protein, PhaR, with Poly[(R)-3-hydroxybutyrate] Film Studied with a Quartz Crystal Microbalance. Biomacromolecules 2006; 7: 2449-54.
    [71] Jendrossek D, Schirmer A, Schlegel HG. Biodegradation of polyhydroxyalkanoic acids. Appl. Microbiol. Biotechnol. 1996; 46: 451-463.
    [72] Briese BH, Schmidt B, Jendrosssek D. Pseudomonas lemoignei has five poly (hydroxyalkanoic acid) (PHA) depolymerase genes: a comparitive study of bacterial and eukaryotic depolymerases. J. Environ. Polym. Degrad. 1994; 2: 75-87.
    [73] Ruiz JA, López NI, Fernández RO, Méndez BS. Polyhydroxyalkanoate degradation is associated with nucleotide accumulation and enhances stress resistance and survival of Pseudomonas oleovorans in natural water microcosms. Appl. Environ. Microbiol. 2001; 67: 225-30.
    [74] Reusch RN, Sparrow AW, Gardiner J. Transport of poly-b-hydroxybutyrate in human plasma. Biochem Biophysics Acta 1992; 1123: 33-40.
    [75] Reusch RN, Sadoff HL. D-poly-β-hydroxybutyrate in membranes of genetically competent bacteria, J. Bacterial 1983; 156: 778-88.
    [76] Chen GQ, Wu Q. Polyhydroxyalkanoates as tissue engineering materials. Biomaterials 2005; 26: 6565-78.
    [77] Hazer B, Steinbüchel A. Increased diversification of polyhydroxyalkanoates by modification reactions for industrial and medical applications. Appl Microbiol Biotechnol 2007; 74: 1-12.
    [78] Tian G, Wu Q, Sun SQ, Noda I, Chen GQ. Study of Thermal melting behavior of microbial polyhydroxyalkanoates using two-dimensional Fourier-transform infrared FT-IR correlation spectroscopy. Appl. Spectroscopy 2001; 55: 888-94.
    [79] Miller ND, Williams DF. On the biodegradation of poly-beta-hydroxybutyrate homopolymer and poly beta-hydroxybutyrate-hydroxyvalerate copolymers. Biomaterials 1987; 8: 129-37.
    [80] Shishatskaya EI, Volova TG, Puzyr AP, Mogilnaya OA and Efremov SN. Tissue response to the implantation of biodegradable polyhydroxyalkanoate sutures. J Mater Sci Mater Med 2004; 15: 719-28.
    [81] Mosahebi A, Fuller P, Wiberg M and Terenghi G. Effect of allogeneic Schwann cell transplantation on peripheral nerve regeneration. Exp Neurol 2002; 173: 213-23.
    [82] Williams SF, Martin DP. Application of PHAs in Medicine and Pharmacy. In: Doi Y, Steinbüchel A, editors. Biopolymers, vol. 10. Weinheim: Wiley-VCH; 2002; 91-121.
    [83] Thomas Freier, Carmen Kunzea, Claudia Nischana, Sven Kramera, Katrin Sternberga, Marko Sa?b, Ullrich T. Hoptb, Klaus-Peter Schmitza. In vitro and in vivo degradation studies for development of a biodegradable patch based on poly (3-hydroxybutyrate). Biomaterials 2002; 23: 2649-57.
    [84] Valappil SP, Misra SK, Boccaccini AR, Roy I. Biomedical applications of polyhydroxyalkanoates, an overview of animal testing and in vivo responses. Expert Rev. Med. Devices 2006; 3: 853-68.
    [85] Misra SK, Valappil SP, Roy I, Boccaccini AR. Polyhydroxyalkanoate (PHA)/inorganic phase composites for tissue engineering applications. Biomacromolecules 2006; 7: 2249-58.
    [86] Anderson AJ, Hayward GW, Williams DR and Dames EA. The production of poly hydroxyalkanoates from unrelated carbon sources. Dawes (ed), Novel biodegradable Microbial Polymetrs, Kluwer Acadimic Publisher 1990; 119-29.
    [87] Heywood GW, Anderson AJ, Williams DR and Dawes EA. Accumulation of poly (hydroxyalkanoate) copolymer containing primarily 3-hydroxyvalerate from simple carbohydrate substrates by Rhodococcus sp. NCIMB 40126. Int. J Biol Macromol 1991; 13: 72-83.
    [88] Caballero K.P., Karel S.F., Register R.A. Biosynthesis and characterizaion of hydroxybutyrate-hydroxycaproate copolymers. Int. J. Biol. Macromol 1995; 17: 86-92.
    [89] Lara L. Madison, Gjalt W. HUISMAN. Metabolic engineering of Poly (3-hydroxyalkanoates): from DNA to plastic. Microbiology and Molecular Biology Reviews 1999; 21-53.
    [90] Sang Y. Lee, Y. Lee, Fulai Wang. Chiral compounds from bacterial polyesters: sugars to plastics to fine chemicals. Biotechnology and bioengineering 1999; 65(3): 363-8.
    [91] Anderson A.J., & Dawes E.A. Occurense, Metabolism, Metabolic Role, and Industrial Use of Bacterial Polyhydroxyalkanoates. Microb. Rev 1990; 54: 450-72.
    [92] Lee S.Y. Bacterial Polyhydroxyalkanoates. Biotech. and Bioeng 1996; 49: 1-14.
    [93] Reusch R.N. Low molecular weight complexed poly (3-hydroxybutyrate): a dynamic and versatile molecule in vivo, Can J Microbiol, 41 (Suppl. 1) 1995; 50-4.
    [94] Sun J, Dai ZW, Zhao Y, Chen GQ. In vitro effect of oligo-hydroxyalkanoates on the growth of mouse fibroblast cell line L929. Biomaterials 2007; 28: 3896-903.
    [95] Martin DP, Peoples OP, Williams SF, Zhong LH. Nutritional and therapeutic uses of 3-hydroxyalkanoate oligomers. US Patent Appl 359086, 1999.
    [96] Lee Y, Park SH, Lim IT, Han K, Lee SY. Preparation of alkyl (R)-(-)-3-hydroxybutyrate by acidic alcoholysis of poly-(R)-(-)-3-hydroxybutyrate. Enzyme Microb. Technol. 2000; 27: 33-6.
    [97] Gao HJ, Wu Q, Chen GQ. A novel genetically engineered pathway for production of D-(-)-3-hydroxybutyric acid by recombinant Escherichia coli. FEMS Microbiol. Lett. 2002; 213: 59-65.
    [98] JN, Ziegler JB. Method of making absorbable surgical sutures from poly beta hydroxyacids. US Patent No: 3225766, 1965.
    [99] Singh S, Maxwell D. Tools of the trade. Best Prac Res Clin Obst Gyn 2006; 20:41-59.
    [100] Knowles JC, Mahmud FA, Hastings GW. Piezoelectric characteristics of a polyhydroxybutyrate-based composite. Clin. Mater 1991; 8: 155-8.
    [101] Ni J, Wang M. In vitro evaluation of hydroxyapatite reinforced polyhydroxybutyrate composite. Mater Sci Eng C-Bio S 2002; 20:101-9.
    [102] Luklinska ZB, Bonfield W. Morphology and ultrastructure of the interface between hydroxyapatite-polyhydroxybutyrate composite implant and bone. J Mater Sci-Mater M 1997; 8:379-83.
    [103] Chen LJ, Wang M. Production and evaluation of biodegradable composites based on PHB-PHV copolymer. Biomaterials 2002; 23:2631-9.
    [104] Wang YW, Wu QO, Chen GQ. Attachment, proliferation and differentiation of osteoblasts on random biopolyester poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds. Biomaterials 2004; 25:669-75.
    [105] Fukuda S, Sakai N, Kamata SE, Nameki H, Kishimoto S, Nishikawa N, Kaneko S, Miyata M, Fujii M, Inuyama Y. Surgical results of skull base surgery for thetreatment of head and neck malignancies involving skull base: multi-institutional studies on 143 cases in Japan. Auris Nasus Larynx 2001; 28: S71-5.
    [106] Bowald SF, Johansson EG. A novel surgical materials. Eurpean Patent No. 0349 505 A2 1990.
    [107] Janousek P, Kabelka Z, Rygl M, Lesny P, Grabec P, Fajstavr J, Jurovcík M, Snajdauf J. Corrosive injury of the oesophagus in children. Int J Ped Otorhinol 2006; 70: 1103-7.
    [108] Qu XH, Wu Q, Liang J, Qu X, Wang SG, Chen GQ. Enhanced vascular-related cellular affinity on surface modified copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate (PHBHHx). Biomaterials 2005; 26:6991-7001.
    [109] Qu XH, Wu Q, Zhang KY, Chen GQ. In vivo studies of poly (3-hydroxybutyrate-co-3- hydroxyhexanoate) based materials: biodegradation and tissue reactions. Biomaterials 2006; 27: 3540-8.
    [110] Qu XH, Wu Q, Liang J, Zou B, Chen GQ. Effect of 3-hydroxyhexanoate content in poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) on in vitro growth and differentiation of smooth muscle cells. Biomaterials 2006; 27:2944-50.
    [111] Qu XH, Wu Q, Chen GQ. In vitro study on hemocompatibility and cytocompatibility of poly (3-hydroxybutyrate-co-3- hydroxyhexanoate). Journal of Biomaterials Science, Polymer Edition 2006; 17: 1107-21.
    [112] Behrend D, Nischan C, Kunze C, Sass M, Schmitz KP. Resorbable scaffold for tissue engineering. Med. Biol. Eng. Comput. 1999; 37: 1510-1.
    [113] Martin DP, Williams SF. Medical applications of poly 4-hydroxybutyrate: a strong flexible absorbable biomaterial. Biochem Eng J 2003; 16: 97-105.
    [114] Sodian R, Loebe M, Hein A, Martin DP, Hoerstrup SP, Potapov EV, Hausmann H, Lueth T, Hetzer R. Application of stereolithography for scaffold fabrication for tissue engineered heart valves. ASAIO J 2002; 48:12-6.
    [115] John L, Foster R, Lenz RW and Clinton R. Fuller Quantitative determination of intracellular depolymerase activity in Pseudomonas oleovorans inclusionscontaining poly-3-hydroxyalkanoates with long alkyl substituents. FEMS Microbiol Lett 1994; 118: 279-82.
    [116] Wang YW, Mo WK, Yao HL, Wu Q, Chen JC, Chen GQ. Biodegradation studies of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate). Polym Degrad Stabil 2004; 85: 815–21.
    [117] Williams SF, Martin DP, Horowitz DM, Peoples OP. PHA applications: addressing the price performance issue I. Tissue engineering. Int J Biol Macromol 1999; 25: 111–21.
    [118] DS Nelson, P Alexander.Immunology of Macrophage.Academic Press 1976; 373.
    [119] Herbert. et a1 . Mannual of macrophage methodology.collection.characterizations, and function. Marcel Dekker Inc 1981; 63.
    [120] P.R. Wood, R.J. Simes, D.S. Nelson. Activity of mouse macrophages purified by adherence to, and removal from, a plastic surface. Journal of Immunological Methods 1979; 28: 117-24.
    [121]李胜亮,陈正堂,金敬顺.肺血管内巨噬细胞的分离、培养及鉴定[J].中华病理学杂志1998; 27(1): 66-67.
    [122]李静,王亚平.大鼠骨髓巨噬细胞的分离,纯化,培养以及鉴定[J].重庆医科大学学报2003; 28(4): 436-439.
    [123]陈秀芳,金丽琴,吕建新.蝉拟青霉对大鼠腹腔及肺泡巨噬细胞的激活作用[J].中国病理生理杂志2002; 18(6): 694-7.
    [124] C. Perez, A. Sanchez, D. Putnam, D. Ting, R. Langer and M. J. Alonso. Poly (lactic acid)-poly (ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA. J Control Release 2001; 75: 211-24.
    [125] Z. Wang, H. Wu, J. Chen, J. Zhang, Y. Yao and G. Q. Chen. A novel self-cleaving phasin tag for purification of recombinant proteins based on hydrophobic polyhydroxyalkanoate nanoparticles. Lab on a chip 2008; 8: 1957-62.
    [126] ZHANG Gang,LU Laichun . Preparation of rhBMP-2-PLA Nanospheres and Observation on Biological Effects. Journal of Oral and Maxillofacial Surgery 2006; 16: 300-06.
    [127] Y. Deng, K. Zhao, X. F. Zhang, P. Hu and G. Q. Chen. Study on the three-dimensional proliferation of rabbit articular cartilage-derived chondrocytes on polyhydroxyalkanoate scaffolds. Biomaterials 2002; 23: 4049–56.
    [128] R. Langer. New methods of drug delivery. Science 1990; 249: 1527-33.
    [129] P. L. Felgner, T. R. Gadek, M. Holm, R. Roman, H. W. Chan, M. Wenz, J. P. Northrop, G. M. Ringold and M. Danielsen. Lipofection: a highly efficient, lipid-mediated DNA-transfection procedure. Proc. Natl. Acad. Sci. USA 1987; 84(21): 7413-7.
    [130] E. Wagner, M. Ogris and W. Zauner, Adv. Polycation-based DNA complexes for tumor-targeted gene delivery in vivo. Drug. Deliv. Rev. 1998; 30: 97.
    [131] J. J. Koh, K. S. Ko, M. Lee, S. Han, J. S. Park and S. W. Kim. Degradable polymeric carrier for the delivery of IL-10 plasmid DNA to prevent autoimmune insulitis of NOD mice. Gene Ther 2000; 7(24): 2099-104.
    [132] J. Haensler and F. C. Jr. Szoka. Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjug. Chem. 1993; 4(5): 372-9.
    [133] O. Boussif, F. Lezoualc'h, M. A. Zanta, M. D. Mergny, D. Scherman, B. Demeneix and J. P. Behr, Proc. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Natl. Acad. Sci, USA 1995; 92: 7297-301.
    [134] V. Y. Alakhov and A. V. Kabanov. Biological agent compositions. Expert Opin Investig Drugs 1998; 7: 1453.
    [135] B. Conti, F. Pavanetto and I. Genta. Use of polylactic acid for the preparation of microparticulate drug delivery systems. Journal of microencapsulation 1992; 9(2): 153-66.
    [136] F. Koosha, R. H. Muller and S. S. Davis. Polyhydroxybutyrate as a drug carrier. Crit Rev Ther Drug Carrier Syst 1989; 6(2): 117-30.
    [137] C. W. Pouton and S. Akhtarb. Biosynthetic polyhydroxyalkanoates and their potential in drug delivery. Adv. Drug Deliv. Rev 1996; 18(2): 133-62.
    [138] M. Zinn, W. Bernard and E. Thomas. Occurrence, synthesis and medical application of bacterial polyhydroxyalkanoate. Adv. Drug Deliv. Rev 2001; 53(1): 5-21.
    [139] D. Y. Kim, H. W. Kim, M. G. Chung and Y. H. Rhee. Biosynthesis, Modification, and Biodegradation of Bacterial Medium-Chain-Length Polyhydroxyalkanoates. J Microbiol 2007; 45:87-97.
    [140] S. L. Xu, R. C. Luo, L. P. Wu, K. T. Xu and G. Q. Chen. Blending and characterizations of microbial poly (3-hydroxybutyrate) with dendrimers. J Appl Polym Sci 2006; 102: 3782-90.
    [141] S. J. Sim, K. D. Snell, S. A. Hogan, J. Stubbe, C. Rha and A. J. Sinskey. PHA synthase activity controls the molecular weight and polydispersity of polyhydroxybutyrate in vivo. Nat Biotechnol 1997; 15: 63-7.
    [142] Y. Y. Shangguan, Y. W. Wang, Q. Wu and G. Q. Chen. The mechanical properties and in vitro biodegradation and biocompatibility of UV-treated poly (3-hydroxybutyrate-co-3-hydroxyhexanoate). Biomaterials 2006; 27: 2349-57.
    [143] Y. Bae, S. Fukushima, A. Harada and K. Kataoka. Design of Environment-Sensitive Supramolecular Assemblies for Intracellular Drug Delivery: Polymeric Micelles that are Responsive to Intracellular pH Change. Angew Chem Int Ed Engl 2003; 42: 4640.
    [144] T. R. Kyriakides, C. Y. Cheung, N. Murthy, P. Bornstein, P. S. Stayton and A. S. Hoffman. pH-Sensitive polymers that enhance intracellular drug delivery in vivo. J Control Release 2002; 78: 295-303.
    [145] H. Kimura, Y. Ogura, T. Moritera, Y. Honda, Y. Tabata and Y. Ikada. In vitro phagocytosis of polylactide microspheres by retinal pigment epithelial cells and intracellular drug release. Current Eye Research 1994; 13: 353-60.
    [146] A. Astier, B. Doat, M. J. Ferrer, G. Benoit, J. Fleury, A. Rolland and R. Leverge. Enhancement of Adriamycin Antitumor Activity by Its Binding with anIntracellular Sustained-Release Form, Polymethacrylate Nanospheres, in U-937 Cells. Cancer Res 1988; 48: 1835-41.
    [147] S. M. Moghimi, A. C. Hunter and J. C. Murray. Long-Circulating and Target-Specific Nanoparticles: Theory to Practice. Pharmacological Reviews 2001; 53: 283-318.
    [148] Alexander V. Kabanov, Pierre Lemieux, Sergey Vinogradov, Valery Alakhov. Pluronic block copolymers: novel functional molecules for gene therapy. Adv. Drug Del. Rev 2002; 54: 223-33.

© 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