双敏感性壳聚糖接枝聚合物的制备及载药性能研究
|
摘要
以具有良好生物相容性和pH敏感性的壳聚糖(CS)为基材,结合可逆加成断裂链转移(RAFT)聚合接枝温敏性聚合物N-异丙基丙烯酰胺(NIPAM),合成一种双敏感的CS接枝聚合物(CS-g-PNIPAM)。用傅里叶红外光谱仪(FT-IR)、扫描电子显微镜(SEM)、透射电镜(TEM)、核磁(H1 NMR)对聚合物的结构和形态进行表征,用变温紫外考察其温敏性,并用来包裹抗癌药物紫杉醇(PTX)。通过物理吸附的方式,将抗癌药物PTX包裹进CS-gNIPAM纳米颗粒(NPs)中制备载药纳米颗粒(CS-g-PNIPAM-PTX)。实验结果表明,CS-g-PNIPAM成功制备,低临界溶解温度(LCST)为30℃,平均粒径为100nm;载药纳米颗粒CS-g-PNIPAM-PTX NPs具有相对较高的药物负载效率(8.1%),在pH=7.4和25℃时,PTX的释放缓慢;但在pH=5.0和37℃时,释放速度大大加快。
A dual sensitive chitosan grafted polymer(CS-g-PNIPAM)was synthesized used chitosan with good biocompatibility and pH sensitivity as the substrate,grafting thermosensitive polymer by combined with reversible addition and fracture chain transfer(RAFT)polymerization.The structure and morphology of grafted polymer was characterized by fourier transform infrared spectroscopy(FT-IR),scanning electron microscopy(SEM),transmission electron microscopy(TEM)and nuclear magnetic resonance(1 H-NMR).The temperature sensitivity of block polymer was investigated by UV irradiation.Used to wrap anticancer drug paclitaxel,the results showed that CS-g-PNIPAM with low critical solution temperature(LCST)of 30℃ and average particle size of 100 nm was successfully prepared.CS-g-PNIPAM-PTX NPs had a relatively high drug loading efficiency(8.1%).At pH 7.4 and 25℃,the release of PTX was slow but significantly accelerated at pH 5.0 and 37℃.
A dual sensitive chitosan grafted polymer(CS-g-PNIPAM)was synthesized used chitosan with good biocompatibility and pH sensitivity as the substrate,grafting thermosensitive polymer by combined with reversible addition and fracture chain transfer(RAFT)polymerization.The structure and morphology of grafted polymer was characterized by fourier transform infrared spectroscopy(FT-IR),scanning electron microscopy(SEM),transmission electron microscopy(TEM)and nuclear magnetic resonance(1 H-NMR).The temperature sensitivity of block polymer was investigated by UV irradiation.Used to wrap anticancer drug paclitaxel,the results showed that CS-g-PNIPAM with low critical solution temperature(LCST)of 30℃ and average particle size of 100 nm was successfully prepared.CS-g-PNIPAM-PTX NPs had a relatively high drug loading efficiency(8.1%).At pH 7.4 and 25℃,the release of PTX was slow but significantly accelerated at pH 5.0 and 37℃.
引文
[1]Tang J,Hua D,Cheng J,et al.Synthesis and properties of temperature-responsive chitosan by controlled free radical polymerization with chitosan-RAFT agent[J].International Iournal of Biological Macromolecules,2008,43(4):383-389.
[2]钱骏,姜晶,曾泽华,等.pH敏感的壳聚糖接枝聚合物的可控合成及载药性能研究[J].合成技术及应用,2011,26(2):19-24.
[3]Jing Z W,Jia Y Y,Wan N,et al.Design and evaluation of novel pH-sensitive ureido-conjugated chitosan/TPP nanoparticles targeted to Helicobacter pylori[J].Biomaterials,2016,84:276-285.
[4]Yang H,Bremner D H,Tao L,et al.Carboxymethyl chitosanmediated synthesis of hyaluronic acid-targeted graphene oxide for cancer drug delivery[J].Carbohydrate Polymers,2016,135:72-78.
[5]Constantin M,Bucatariu S M,Doroftei F,et al.Smart composite materials based on chitosan microspheres embedded in thermosensitive hydrogel for controlled delivery of drugs[J].Carbohydrate Polymers,2017,157:493-502.
[6]Wang Y,Xu H,Wang J,et al.Development of a thermally responsive nanogel based on chitosan-poly(N-isopropylacrylamide-co-acrylamide)for paclitaxel delivery[J].Journal of Pharmaceutical Sciences,2014,103(7):2012-2021.
[7]Dai T,Li N,Han F,et al.AMP-guided tumour-specific nanoparticle delivery via adenosine A 1receptor[J].Biomaterials,2016,83:37-50.
[8]Zhong Y,Goltsche K,Cheng L,et al.Hyaluronic acid-shelled acid-activatable paclitaxel prodrug micelles effectively target and treat CD44-overexpressing human breast tumor xenografts in vivo[J].Biomaterials,2016,84:250-261.
[9]Fan L,Zhang Y,Wang F,et al.Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs[J].Biomaterials,2016,76:399-407.
[10]Jiang J,Hua D,Tang J.One-pot synthesis of pH-and thermosensitive chitosan-based nanoparticles by the polymerization of acrylic acid/chitosan with macro-RAFT agent[J].International Journal of Biological Macromolecules,2010,46(1):126-130.
[11]齐旭,刘佩,李速明,等.聚乳酸-聚乙二醇三嵌段共聚物包载紫杉醇纳米胶束的制备及其体外药物释放行为[J].复旦学报:自然科学版,2013,52(1):1-8.
[12]Zhong Y,Goltsche K,Cheng L,et al.Hyaluronic acid-shelled acid-activatable paclitaxel prodrug micelles effectively target and treat CD44-overexpressing human breast tumor xenografts in vivo[J].Biomaterials,2016,84:250-261.
[13]DeSantis C,Ma J,Bryan L,et al.Breast cancer statistics,2013[J].CA:A Cancer Journal for Clinicians,2014,64(1):52-62.
[14]Palumbo R,Sottotetti F,Bernardo A.Targeted chemotherapy with nanoparticle albumin-bound paclitaxel(nab-paclitaxel)in metastatic breast cancer:which benefit for which patients?[J].Therapeutic Advances in Medical Oncology,2016,8(3):209-229.
[15]Kim Y,Dalhaimer P,Christian D,et al.Polymeric worm micelles as nano-carriers for drug delivery[J].Nanotechnology,2005,16(7):484-491.
[16]孙达峰,朱昌玲,张卫明,等.N-乙酰化反应制备水溶性壳聚糖研究[J].中国野生植物资源,2010,29(6):48-50.
[17]Hua D,Tang J,Cheng J,et al.A novel method of controlled grafting modification of chitosan via RAFT polymerization using chitosan-RAFT agent[J].Carbohydrate Polymers,2008,73(1):98-104.
[2]钱骏,姜晶,曾泽华,等.pH敏感的壳聚糖接枝聚合物的可控合成及载药性能研究[J].合成技术及应用,2011,26(2):19-24.
[3]Jing Z W,Jia Y Y,Wan N,et al.Design and evaluation of novel pH-sensitive ureido-conjugated chitosan/TPP nanoparticles targeted to Helicobacter pylori[J].Biomaterials,2016,84:276-285.
[4]Yang H,Bremner D H,Tao L,et al.Carboxymethyl chitosanmediated synthesis of hyaluronic acid-targeted graphene oxide for cancer drug delivery[J].Carbohydrate Polymers,2016,135:72-78.
[5]Constantin M,Bucatariu S M,Doroftei F,et al.Smart composite materials based on chitosan microspheres embedded in thermosensitive hydrogel for controlled delivery of drugs[J].Carbohydrate Polymers,2017,157:493-502.
[6]Wang Y,Xu H,Wang J,et al.Development of a thermally responsive nanogel based on chitosan-poly(N-isopropylacrylamide-co-acrylamide)for paclitaxel delivery[J].Journal of Pharmaceutical Sciences,2014,103(7):2012-2021.
[7]Dai T,Li N,Han F,et al.AMP-guided tumour-specific nanoparticle delivery via adenosine A 1receptor[J].Biomaterials,2016,83:37-50.
[8]Zhong Y,Goltsche K,Cheng L,et al.Hyaluronic acid-shelled acid-activatable paclitaxel prodrug micelles effectively target and treat CD44-overexpressing human breast tumor xenografts in vivo[J].Biomaterials,2016,84:250-261.
[9]Fan L,Zhang Y,Wang F,et al.Multifunctional all-in-one drug delivery systems for tumor targeting and sequential release of three different anti-tumor drugs[J].Biomaterials,2016,76:399-407.
[10]Jiang J,Hua D,Tang J.One-pot synthesis of pH-and thermosensitive chitosan-based nanoparticles by the polymerization of acrylic acid/chitosan with macro-RAFT agent[J].International Journal of Biological Macromolecules,2010,46(1):126-130.
[11]齐旭,刘佩,李速明,等.聚乳酸-聚乙二醇三嵌段共聚物包载紫杉醇纳米胶束的制备及其体外药物释放行为[J].复旦学报:自然科学版,2013,52(1):1-8.
[12]Zhong Y,Goltsche K,Cheng L,et al.Hyaluronic acid-shelled acid-activatable paclitaxel prodrug micelles effectively target and treat CD44-overexpressing human breast tumor xenografts in vivo[J].Biomaterials,2016,84:250-261.
[13]DeSantis C,Ma J,Bryan L,et al.Breast cancer statistics,2013[J].CA:A Cancer Journal for Clinicians,2014,64(1):52-62.
[14]Palumbo R,Sottotetti F,Bernardo A.Targeted chemotherapy with nanoparticle albumin-bound paclitaxel(nab-paclitaxel)in metastatic breast cancer:which benefit for which patients?[J].Therapeutic Advances in Medical Oncology,2016,8(3):209-229.
[15]Kim Y,Dalhaimer P,Christian D,et al.Polymeric worm micelles as nano-carriers for drug delivery[J].Nanotechnology,2005,16(7):484-491.
[16]孙达峰,朱昌玲,张卫明,等.N-乙酰化反应制备水溶性壳聚糖研究[J].中国野生植物资源,2010,29(6):48-50.
[17]Hua D,Tang J,Cheng J,et al.A novel method of controlled grafting modification of chitosan via RAFT polymerization using chitosan-RAFT agent[J].Carbohydrate Polymers,2008,73(1):98-104.