壳聚糖载药系统及其在骨组织工程中的应用
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摘要
甲壳素作为天然高分子物质在自然界中含量仅次于纤维素,其经脱乙酰化反应后所得的产物壳聚糖,是唯一的天然碱性多糖。壳聚糖具有良好的生物相容性和生物可降解性。以壳聚糖为基质的载药体系具有提高药物生物利用度、改变给药方式和控制释放等优点。本文总结了基于壳聚糖的载药体系的研究进展及其在骨组织工程的应用,并总结所存在的问题和发展前景。
As a natural macromoleculematerial, chitin is the second most abundant natural resource after cellulose. Chitosan is the diacylation product of chitin. It is the only naturalalkaline polysaccharide,which possesses excellent properties of biocompatibility and biodegradability. The drug delivery systems based on chitosan are proved to have the advantages of improving the drug bioavailability, changing its delivery mode and controlling drug release. This review summarizes the research progress of chitosan-based drug delivery systems and its applications in bone tissue engineering as well as its problems and development prospects.
As a natural macromoleculematerial, chitin is the second most abundant natural resource after cellulose. Chitosan is the diacylation product of chitin. It is the only naturalalkaline polysaccharide,which possesses excellent properties of biocompatibility and biodegradability. The drug delivery systems based on chitosan are proved to have the advantages of improving the drug bioavailability, changing its delivery mode and controlling drug release. This review summarizes the research progress of chitosan-based drug delivery systems and its applications in bone tissue engineering as well as its problems and development prospects.
引文
[1] Sinha VR,Singla AK,Wadhawan S,et al.Chitosan microspheres as a potential carrier for drugs[J].Int J Pharm,2004,274(1):1-33.
[2] Velasco MA.Design,materials and mechanobiology of biodegra-dable scaffolds for bone tissue engineering[J].Biomed Res Int,2015,2015(1-6):729076.
[3] Elgadir MA,Uddin MS,Ferdosh S,et al.Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems:a review[J].J Food Drug Anal,2015,23(4):619-629.
[4] Bernkop-Schnürch A,Dünnhaupt S.Chitosan-based drug delivery systems[J].Eur J Pharm Biopharm,2012,81(3):463-469.
[5] Vilar G,Tullapuche J,Albericio F.Polymers and drug delivery systems[J].Curr Drug Deliv,2012,9(4):367-394.
[6] Mumper RJ,Wang J,Claspell JM,et al.Novel polymeric condensing carriers for gene delivery[J].Proceed Intern Symp Control Rel Bioact Mater,1995,22:178-179.
[7] Varde NK,Pack DW.Microspheres for controlled release drug delivery[J].Expert Opin Biol Ther,2004,4(1):35-51.
[8] Casettari L,Illum L.Chitosan in nasal delivery systems for therapeutic drugs[J].J Control Release,2014,190:189-200.
[9] Farooq U,Malviya R,Sharma PK.Advancement in microsphere preparation using natural polymers and recent patents[J].Recent Pat Drug Deliv Formul,2014,8(2):367-394.
[10] Pichayakorn W,Boonme P.Evaluation of cross-linked chitosan microparticles containing metronidazole for periodontitis treatment[J].Mater Sci Eng C Mater Biol Appl,2013,33(3):1197-1202.
[11] Szymańska E,Winnicka K.Preparation and in vitro evaluation of chitosan microgranules with clotrimazole[J].Acta Poloniae Pharmaceutica,2012,69(3):509-513.
[12] Wang H,Xu Y,Zhou X.Docetaxel-loaded chitosan microspheres as a lung targeted drug delivery system:in vitro and in vivo evaluation[J].Int J Mol Sci,2014,15(3):3519-3532.
[13] Premaletha K,Licy CD,Jose S,et al.Formulation,characterization and optimization of hepatitis B surface antigen (HBsAg)-loaded chitosan microspheres for oral delivery[J].Pharm Dev Technol,2012,17(2):251-258.
[14] Wu G,Feng C,Hui G,et al.Improving the osteogenesis of rat mesenchymal stem cells by chitosan-based-microRNA nanoparticles[J].Carbohydr Polym,2016,138:49-58.
[15] Liang Z,Zhu B,Jia Y,et al.Preparation of biocompatible carboxymethyl chitosan nanoparticles for delivery of antibiotic drug[J].Biomed Res Int,2013,2013(3):236469.
[16] Mao HQ,Roy K,Troung-Le VL,et al.Chitosan-DNA nanoparticles as gene carriers:synthesis,characterization and transfection efficiency[J].J Controlled Release,2001,70(3):399-421.
[17] Feng C,Wang Z,Jiang C,et al.Chitosan/o-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery:in vitro and in vivo evaluation[J].Int J Pharm,2013,457(1):158-167.
[18] Ragelle H,Riva R,Vandermeulen G,et al.Chitosan nanoparti-cles for siRNA delivery:optimizing formulation to increase stability and efficiency[J].J Controlled Release,2014,176(3):54-63.
[19] Chaiyasan W,Srinivas SP,Tiyaboonchai W.Mucoadhesive chitosan-dextran sulfate nanoparticles for sustained drug delivery to the ocular surface[J].J Ocul Pharmacol Ther,2013,29(2):200-207.
[20] Ignatova M,Manolova N,Rashkov I.Electrospun antibacterial chitosan-based fibers[J].Macromol Biosci,2013,13(7):860-872.
[21] Bertoncelj V,Pelipenko J,Kristl J,et al.Development and bioevaluation of nanofibers with blood-derived growth factors for dermal wound healing[J].Eur J Pharm Biopharm,2014,88(1):64-74.
[22] Lancina MG,Shankar RK,Yang H.Chitosan nanofibers for transbuccal insulin delivery[J].J Biomed Mater Res A,2017,105(5):1252-1259.
[23] Bhattarai N,Gunn J,Zhang M.Chitosan-based hydrogels for controlled,localized drug delivery[J].Adv Drug Deliv Rev,2010,62(1):83-99.
[24] Jiang G,Sun J,Ding F.PEG-g-chitosan thermosensitive hydrogel for implant drug delivery:cytotoxicity,in vivo degradation and drug release[J].J Biomater Sci Polym Ed,2014,25(3):241-256.
[25] Mukhopadhyay P,Sarkar K,Bhattacharya S,et al.pH sensitive N-succinyl chitosan grafted polyacrylamide hydrogel for oral insulin delivery[J].Carbohydr Polym,2014,112(2):627-637.
[26] Gu C,Le V,Lang M,et al.Preparation of polysaccharide derivates chitosan-graft-poly(?-caprolactone) amphiphilic copolymer micelles for 5-fluorouracil drug delivery[J].Colloids Surf B Biointerfaces,2014,116:745-750.
[27] Hermans K,Van den Plas D,Kerimova S,et al.Development and characterization of mucoadhesive chitosan films for ophthalmic delivery of cyclosporine A[J].Int J Pharm,2014,472(1/2):10-19.
[28] Huang D,Zuo Y,Zou Q,et al.Antibacterial chitosan coating on nano-hydroxyapatite/polyamide66 porous bone scaffold for drug delivery[J].J Biomater Sci Polym Ed,2011,22(7):931-944.
[29] Cui X,Gu Y,Wang H,et al.In vitro bioactivity,cytocompatibility,and antibiotic release profile;of gentamicin sulfate-loaded borate bioactive glass/chitosan composites[J].J Mater Sci Mater Med,2013,24(10):2391-2403.
[30] Kim SE,Dong HS,Yun YP,et al.Local delivery of alendronate eluting chitosan scaffold can effectively increase osteoblast functions and inhibit osteoclast differentiation[J].J Mater Sci Mater Med,2012,23(11):2739-2749.
[31] Leena RS,Vairamani M,Selvamurugan N.Alginate/Gelatin scaffolds incorporated with Silibinin-loaded Chitosan nanoparticles for bone formation in vitro[J].Colloids Surf B Biointerfaces,2017,158:308-318.
[32] Li Q,Zhou G,Yu X,et al.Porous deproteinized bovine bone scaffold with three-dimensional localized drug delivery system using chitosan microspheres[J].Biomed Eng Online,2015,14(1):33.
[33] Mc Laughlin SW,Cui Z,Starnes T,et al.Injectable thermogelling chitosan for the local delivery of bone morphogenetic protein[J].J Mater Sci Mater Med,2012,23(9):2141-2149.
[34] De RB.Local controlled release of VEGF and PDGF from a combined brushite-chitosan system enhances bone regeneration[J].J Control Release,2010,143(1):45-52.
[35] Kim S,Kang Y,Krueger CA,et al.Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation[J].Acta Biomater,2012,8(5):1768-1777.
[36] Fang Y,Chen X,Wt G.Gene delivery in tissue engineering and regenerative medicine[J].J Biomed Mater Res B Appl Biomater,2015,103(8):1679-1699.
[37] Hui L,Ji Q,Yan S,et al.Accelerated bony defect healing based on chitosan thermosensitive hydrogel scaffolds embedded with chitosan nanoparticles for the delivery of BMP2 plasmid DNA[J].J Biomed Mater Res A,2016,105(1):265-273.
[38] Chen X,Gu S,Chen B F,et al.Nanoparticle delivery of stable miR-199a-5p agomir improves the osteogenesis of human mesenchymal stem cells via the HIF1a pathway[J].Biomaterials,2015,53:239-250.
[39] Ma Z,Yang C,Song W,et al.Chitosan hydrogel as siRNA vector for prolonged gene silencing[J].J Nanobiotechnology,2014,12(1):1-9.
[40] Jia S,Yang X,Song W,et al.Incorporation of osteogenic and angiogenic small interfering RNAs into chitosan sponge for bone tissue engineering[J].Int J Nanomedicine,2014,2014(Issue 1):5307-5316.
[41] Bae IH,Jeong BC,Kook MS,et al.Evaluation of a thiolated chitosan scaffold for local delivery of BMP-2 for osteogenic differentiation and ectopic bone formation[J].Biomed Res Int,2013(371):878930.
[2] Velasco MA.Design,materials and mechanobiology of biodegra-dable scaffolds for bone tissue engineering[J].Biomed Res Int,2015,2015(1-6):729076.
[3] Elgadir MA,Uddin MS,Ferdosh S,et al.Impact of chitosan composites and chitosan nanoparticle composites on various drug delivery systems:a review[J].J Food Drug Anal,2015,23(4):619-629.
[4] Bernkop-Schnürch A,Dünnhaupt S.Chitosan-based drug delivery systems[J].Eur J Pharm Biopharm,2012,81(3):463-469.
[5] Vilar G,Tullapuche J,Albericio F.Polymers and drug delivery systems[J].Curr Drug Deliv,2012,9(4):367-394.
[6] Mumper RJ,Wang J,Claspell JM,et al.Novel polymeric condensing carriers for gene delivery[J].Proceed Intern Symp Control Rel Bioact Mater,1995,22:178-179.
[7] Varde NK,Pack DW.Microspheres for controlled release drug delivery[J].Expert Opin Biol Ther,2004,4(1):35-51.
[8] Casettari L,Illum L.Chitosan in nasal delivery systems for therapeutic drugs[J].J Control Release,2014,190:189-200.
[9] Farooq U,Malviya R,Sharma PK.Advancement in microsphere preparation using natural polymers and recent patents[J].Recent Pat Drug Deliv Formul,2014,8(2):367-394.
[10] Pichayakorn W,Boonme P.Evaluation of cross-linked chitosan microparticles containing metronidazole for periodontitis treatment[J].Mater Sci Eng C Mater Biol Appl,2013,33(3):1197-1202.
[11] Szymańska E,Winnicka K.Preparation and in vitro evaluation of chitosan microgranules with clotrimazole[J].Acta Poloniae Pharmaceutica,2012,69(3):509-513.
[12] Wang H,Xu Y,Zhou X.Docetaxel-loaded chitosan microspheres as a lung targeted drug delivery system:in vitro and in vivo evaluation[J].Int J Mol Sci,2014,15(3):3519-3532.
[13] Premaletha K,Licy CD,Jose S,et al.Formulation,characterization and optimization of hepatitis B surface antigen (HBsAg)-loaded chitosan microspheres for oral delivery[J].Pharm Dev Technol,2012,17(2):251-258.
[14] Wu G,Feng C,Hui G,et al.Improving the osteogenesis of rat mesenchymal stem cells by chitosan-based-microRNA nanoparticles[J].Carbohydr Polym,2016,138:49-58.
[15] Liang Z,Zhu B,Jia Y,et al.Preparation of biocompatible carboxymethyl chitosan nanoparticles for delivery of antibiotic drug[J].Biomed Res Int,2013,2013(3):236469.
[16] Mao HQ,Roy K,Troung-Le VL,et al.Chitosan-DNA nanoparticles as gene carriers:synthesis,characterization and transfection efficiency[J].J Controlled Release,2001,70(3):399-421.
[17] Feng C,Wang Z,Jiang C,et al.Chitosan/o-carboxymethyl chitosan nanoparticles for efficient and safe oral anticancer drug delivery:in vitro and in vivo evaluation[J].Int J Pharm,2013,457(1):158-167.
[18] Ragelle H,Riva R,Vandermeulen G,et al.Chitosan nanoparti-cles for siRNA delivery:optimizing formulation to increase stability and efficiency[J].J Controlled Release,2014,176(3):54-63.
[19] Chaiyasan W,Srinivas SP,Tiyaboonchai W.Mucoadhesive chitosan-dextran sulfate nanoparticles for sustained drug delivery to the ocular surface[J].J Ocul Pharmacol Ther,2013,29(2):200-207.
[20] Ignatova M,Manolova N,Rashkov I.Electrospun antibacterial chitosan-based fibers[J].Macromol Biosci,2013,13(7):860-872.
[21] Bertoncelj V,Pelipenko J,Kristl J,et al.Development and bioevaluation of nanofibers with blood-derived growth factors for dermal wound healing[J].Eur J Pharm Biopharm,2014,88(1):64-74.
[22] Lancina MG,Shankar RK,Yang H.Chitosan nanofibers for transbuccal insulin delivery[J].J Biomed Mater Res A,2017,105(5):1252-1259.
[23] Bhattarai N,Gunn J,Zhang M.Chitosan-based hydrogels for controlled,localized drug delivery[J].Adv Drug Deliv Rev,2010,62(1):83-99.
[24] Jiang G,Sun J,Ding F.PEG-g-chitosan thermosensitive hydrogel for implant drug delivery:cytotoxicity,in vivo degradation and drug release[J].J Biomater Sci Polym Ed,2014,25(3):241-256.
[25] Mukhopadhyay P,Sarkar K,Bhattacharya S,et al.pH sensitive N-succinyl chitosan grafted polyacrylamide hydrogel for oral insulin delivery[J].Carbohydr Polym,2014,112(2):627-637.
[26] Gu C,Le V,Lang M,et al.Preparation of polysaccharide derivates chitosan-graft-poly(?-caprolactone) amphiphilic copolymer micelles for 5-fluorouracil drug delivery[J].Colloids Surf B Biointerfaces,2014,116:745-750.
[27] Hermans K,Van den Plas D,Kerimova S,et al.Development and characterization of mucoadhesive chitosan films for ophthalmic delivery of cyclosporine A[J].Int J Pharm,2014,472(1/2):10-19.
[28] Huang D,Zuo Y,Zou Q,et al.Antibacterial chitosan coating on nano-hydroxyapatite/polyamide66 porous bone scaffold for drug delivery[J].J Biomater Sci Polym Ed,2011,22(7):931-944.
[29] Cui X,Gu Y,Wang H,et al.In vitro bioactivity,cytocompatibility,and antibiotic release profile;of gentamicin sulfate-loaded borate bioactive glass/chitosan composites[J].J Mater Sci Mater Med,2013,24(10):2391-2403.
[30] Kim SE,Dong HS,Yun YP,et al.Local delivery of alendronate eluting chitosan scaffold can effectively increase osteoblast functions and inhibit osteoclast differentiation[J].J Mater Sci Mater Med,2012,23(11):2739-2749.
[31] Leena RS,Vairamani M,Selvamurugan N.Alginate/Gelatin scaffolds incorporated with Silibinin-loaded Chitosan nanoparticles for bone formation in vitro[J].Colloids Surf B Biointerfaces,2017,158:308-318.
[32] Li Q,Zhou G,Yu X,et al.Porous deproteinized bovine bone scaffold with three-dimensional localized drug delivery system using chitosan microspheres[J].Biomed Eng Online,2015,14(1):33.
[33] Mc Laughlin SW,Cui Z,Starnes T,et al.Injectable thermogelling chitosan for the local delivery of bone morphogenetic protein[J].J Mater Sci Mater Med,2012,23(9):2141-2149.
[34] De RB.Local controlled release of VEGF and PDGF from a combined brushite-chitosan system enhances bone regeneration[J].J Control Release,2010,143(1):45-52.
[35] Kim S,Kang Y,Krueger CA,et al.Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation[J].Acta Biomater,2012,8(5):1768-1777.
[36] Fang Y,Chen X,Wt G.Gene delivery in tissue engineering and regenerative medicine[J].J Biomed Mater Res B Appl Biomater,2015,103(8):1679-1699.
[37] Hui L,Ji Q,Yan S,et al.Accelerated bony defect healing based on chitosan thermosensitive hydrogel scaffolds embedded with chitosan nanoparticles for the delivery of BMP2 plasmid DNA[J].J Biomed Mater Res A,2016,105(1):265-273.
[38] Chen X,Gu S,Chen B F,et al.Nanoparticle delivery of stable miR-199a-5p agomir improves the osteogenesis of human mesenchymal stem cells via the HIF1a pathway[J].Biomaterials,2015,53:239-250.
[39] Ma Z,Yang C,Song W,et al.Chitosan hydrogel as siRNA vector for prolonged gene silencing[J].J Nanobiotechnology,2014,12(1):1-9.
[40] Jia S,Yang X,Song W,et al.Incorporation of osteogenic and angiogenic small interfering RNAs into chitosan sponge for bone tissue engineering[J].Int J Nanomedicine,2014,2014(Issue 1):5307-5316.
[41] Bae IH,Jeong BC,Kook MS,et al.Evaluation of a thiolated chitosan scaffold for local delivery of BMP-2 for osteogenic differentiation and ectopic bone formation[J].Biomed Res Int,2013(371):878930.