- 无标题文档
查看论文信息

中文题名:

 

纳米羟基磷灰石粉体的微波水热法制备及其负载抗骨肉瘤药物的研究

    

姓名:

 陈正雄    

学号:

 1049721800191    

保密级别:

 公开    

论文语种:

 chi    

学科代码:

 080500    

学科名称:

 工学 - 材料科学与工程    

学生类型:

 硕士    

学校:

 武汉理工大学    

院系:

 材料科学与工程学院    

专业:

 材料科学与工程    

研究方向:

 生物医用材料    

第一导师姓名:

 王欣宇    

第一导师院系:

 材料科学与工程学院    

完成日期:

 2022-06-27    

答辩日期:

 2021-12-02    

中文关键词:

 

纳米材料 ; 羟基磷灰石 ; 氨基酸 ; 阿霉素 ; 骨肉瘤

    

中文摘要:

羟基磷灰石(HA)有着良好的的生物相容性、生物学活性,同时也具有一定的骨诱导性,羟基磷灰石作为人体骨组织最主要的的无机成分之一受到了人们的广泛关注并且应用在骨组织修复和骨缺损的填充过程中。虽然纳米羟基磷灰石粉体本身具有良好的生物相容性,但也存在一定的纳米细胞毒性。为避免上述问题,本论文通过微波水热法高效大量制备了氨基酸改性的纳米羟基磷灰石粉体,所制得的粉体具有晶粒尺寸小,长径比低,形貌十分均匀的特点,并且细胞毒性较小,然后将阿霉素(DOX)负载到羟基磷灰石粉体上,发现对骨肉瘤细胞具有一定的抑制作用。

       (1)通过微波水热法,研究了反应的pH以及不同氨基酸投料比对生成的羟基磷灰石粉体的影响。结果表明,保持反应温度为160℃,保温反应时间为40 min,所制得的纳米羟基磷灰石粉体为棒状,当氨基酸与钙离子的摩尔比为1.5时纳米粒子长度为64.7±13.6nm,直径为29.1±3.9nm。

(2)不同氨基酸投料比对羟基磷灰石的晶粒尺寸以及分散性有影响,因此通过不同浓度氨基酸改性的羟基磷灰石粉体的比表面积存在差异,通过制得的纳米羟基磷灰石粉体作为药物载体负载阿霉素(DOX),研究了不同氨基酸改性的羟基磷灰石粉体的载药能力以及对骨肉瘤细胞的抑制作用。苏氨酸改性的羟基磷灰石粉体负载阿霉素后有较明显的抑制骨肉瘤的作用。

(3)利用微波水热法制备不同氨基酸改性的纳米羟基磷灰石粉体,通过形貌分析和体外细胞实验,我们发现苏氨酸改性的羟基磷灰石粉体对小鼠成骨细胞的毒性较小,同时对骨肉瘤细胞有较明显的抑制作用。

参考文献:

[1]Kasaj, Adrian, Brita Willershausen, et al. Human Periodontal Fibroblast Response to a Nanostructured Hydroxyapatite Bone Replacement Graft in Vitro[J]. Archives of Oral Biology, 2008, 6(4):83-89.

[2]Ximei, Wen, Zhang Jun, et al. Preparation of Hydroxyapatite Whiskers by Hydrothermal Treatment[J]. China Ceramics Lan, 2008, 5(3):56-68.

[3]Wei, Xue, and Matthew Z. Yates. Yttrium-Doped Hydroxyapatite Membranes with High Proton Conductivity[J]. Chemistry of Materials, 2012, 17(10):38-43.

[4]Saha, R., M. Bose, S. Sen Santara, J. Roy, and S. Adak. Identification of Proximal and Distal Axial Ligands in Leishmania Major Pseudoperoxidase[J]. Biochemistry, 2013, 8(4):78-87.

[5]Dey, S., M. Das, and V. K. Balla. Effect of Hydroxyapatite Particle Size, Morphology and Crystallinity on Proliferation of Colon Cancer Hct116 Cells[J]. Mater Sci Eng C Mater Biol Appl, 2014, 33(39):6-9.

[6]Joao, Carlos, Rute Almeida, Jorge Silva, and João Borges. A Simple Sol-Gel Route to the Construction of Hydroxyapatite Inverted Colloidal Crystals for Bone Tissue Engineering[J]. Materials Letters, 2016, 40(18):7-10.

[7]Melcher, M., S. J. Facey, T. M. Henkes, T. Subkowski, and B. Hauer. Accelerated Nucleation of Hydroxyapatite Using an Engineered Hydrophobin Fusion Protein[J]. Biomacromolecules, 2016, 17(5):16-26.

[8]Park, So Yeon, Kyung-Il Kim, Sung Pyo Park, Jung Heon Lee, and Hyun Suk Jung. Aspartic Acid-Assisted Synthesis of Multifunctional Strontium-Substituted Hydroxyapatite Microspheres[J]. Crystal Growth & Design, 2016, 43(8):18-26.

[9]Samadikuchaksaraei, Ali, Mazaher Gholipourmalekabadi, et al. Fabrication Andin Vivoevaluation of an Osteoblast-Conditioned Nano-Hydroxyapatite/Gelatin Composite Scaffold for Bone Tissue Regeneration[J]. Journal of Biomedical Materials Research Part A, 2016, 6(8):1-10.

[10]Saranya, Sundarraj, Selvaraj Joseph Samuel Justin, Rajadurai Vijay Solomon, and Paul Wilson. L-Arginine Directed and Ultrasonically Aided Growth of Nanocrystalline Hydroxyapatite Particles with Tunable Morphology[J]. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2018, 12(2):70-79.

[11]Szczes, A., L. Holysz, and E. Chibowski. Synthesis of Hydroxyapatite for Biomedical Applications[J]. Adv Colloid Interface Sci, 2017, 9(3):21-30.

[12]Wang, J., and L. L. Shaw. Nanocrystalline Hydroxyapatite with Simultaneous Enhancements in Hardness and Toughness[J]. Biomaterials, 2009, 12(7):65-72.

[13]He, Z., J. Ma, and C. Wang. Constitutive Modeling of the Densification and the Grain Growth of Hydroxyapatite Ceramics[J]. Biomaterials, 2005, 8(6):13-21.

[14]Varadavenkatesan, Thivaharan, Ramesh Vinayagam, Shraddha Pai. Synthesis, Biological and Environmental Applications of Hydroxyapatite and Its Composites with Organic and Inorganic Coatings[J]. Progress in Organic Coatings, 2021, 12(4):59-68.

[15]Suntornsaratoon, Panan, Narattaphol Charoenphandhu, and Nateetip Krishnamra. Fortified Tuna Bone Powder Supplementation Increases Bone Mineral Density of Lactating Rats and Their Offspring[J]. Biomaterials, 2018, 20(5):27-34.

[16]Cai, Zhengwei, Xinyu Wang, Zongrui Zhang, Yingchao Han, Jing Luo, Mingzheng Huang, BoWen Zhang, and Yuanjing Hou. Large-Scale and Fast Synthesis of Nano-Hydroxyapatite Powder by a Microwave-Hydrothermal Method[J]. RSC Advances, 2019, 24(12):23-30.

[17]Coskuner-Weber, O., and V. N. Uversky. Alanine Scanning Effects on the Biochemical and Biophysical Properties of Intrinsically Disordered Proteins: A Case Study of the Histidine to Alanine Mutations in Amyloid-Beta42[J]. J Chem Inf Model, 2019, 8(2):71-84.

[18]Tao, J., Y. Shin, R. Jayasinha, G. W. Buchko, S. D. Burton, A. C. Dohnalkova, Z. Wang, W. J. Shaw, and B. J. Tarasevich. The Energetic Basis for Hydroxyapatite Mineralization by Amelogenin Variants Provides Insights into the Origin of Amelogenesis Imperfecta[J]. Proc Natl Acad Sci U S A, 2019, 13(9):67-72.

[19]Zhu, Lifei, Yu Fang, Zhixiang Ding, Shuyan Zhang, and Xiaoyuan Wang. Developing an L-Threonine-Producing Strain from Wild-Type Escherichia Coli by Modifying the Glucose Uptake, Glyoxylate Shunt, and L-Threonine Biosynthetic Pathway[J]. Biotechnology and Applied Biochemistry, 2019, 9(6):62-76.

[20]Chen, Jia, Jiawei Liu, Haishan Deng, Shun Yao, and Youfa Wang. Regulatory Synthesis and Characterization of Hydroxyapatite Nanocrystals by a Microwave-Assisted Hydrothermal Method[J]. Ceramics International, 2020, 21(2):85-93.

[21]Veiga, Anabela, Filipa Castro, Fernando Rocha, and Ana L. Oliveira. Protein-Based Hydroxyapatite Materials: Tuning Composition toward Biomedical Applications[J]. ACS Applied Bio Materials, 2020, 7(9):41-55.

[22]Calabrese, G., S. Petralia, D. Franco, G. Nocito, C. Fabbi, L. Forte, S. Guglielmino, S. Squarzoni, F. Traina, and S. Conoci. A New Ag-Nanostructured Hydroxyapatite Porous Scaffold: Antibacterial Effect and Cytotoxicity Study[J]. Mater Sci Eng C Mater Biol Appl, 2021, 9(4):44-53.

[23]Kuznetsova, T., V. Lapitskaya, J. Solovjov, S. Chizhik, V. Pilipenko, and S. Aizikovich. Properties of Crsi2 Layers Obtained by Rapid Heat Treatment of Cr Film on Silicon[J]. Nanomaterials (Basel), 2021, 12(7):36-45.

[24]Mendes, Gilberto de Oliveira, Thomas Dyer, Laszlo Csetenyi, and Geoffrey Michael Gadd. Rock Phosphate Solubilization by Abiotic and Fungal-Produced Oxalic Acid: Reaction Parameters and Bioleaching Potential[J]. Microbial Biotechnology, 2021, 5(7):79-86.

[25]Sans, Jordi, Vanesa Sanz, Luis J. del Valle, Jordi Puiggali, Pau Turon, and Carlos Aleman. Implications for the Electrophotosynthesis of Amino Acids by Nitrogen and Carbon Fixation[J]. Journal of Catalysis, 2021, 7(4):98-107.

[26]Xiong, Y., J. Huang, L. Fu, H. Ren, S. Li, W. Xia, and Y. Yan. Enhancement of Osteoblast Cells Osteogenic Differentiation and Bone Regeneration by Hydroxyapatite/Phosphoester Modified Poly(Amino Acid)[J]. Mater Sci Eng C Mater Biol Appl, 2020, 10(7):73-82.

[27]Morakul, S., Y. Otsuka, K. Ohnuma, M. Tagaya, S. Motozuka, Y. Miyashita, and Y. Mutoh. Enhancement Effect on Antibacterial Property of Gray Titania Coating by Plasma-Sprayed Hydroxyapatite-Amino Acid Complexes During Irradiation with Visible Light[J]. Heliyon, 2019, 8(3):23-31.

[28]Dai, Hongliang, Xinwei Tan, Hui Zhu, Tongshuai Sun, and Xingang Wang. Effects of Commonly Occurring Metal Ions on Hydroxyapatite Crystallization for Phosphorus Recovery from Wastewater[J]. Water, 2018, 11(4):92-97.

[29]Bajkowski, A. S., and H. C. Friedmann. Delta-Aminolevulinic Acid Formation. Purification and Properties of Alanine:4,5-Dioxovalerate, Aminotransferase and Isolation of 4,5-Dioxovalerate from Clostridium Tetanomorphum[J]. Journal of Biological Chemistry, 1982, 22(5):7-11.

[30]Zhou, J., B. Li, S. Lu, L. Zhang, and Y. Han. Regulation of Osteoblast Proliferation and Differentiation by Interrod Spacing of Sr-Ha Nanorods on Microporous Titania Coatings[J]. ACS Appl Mater Interfaces, 2013, 11(6):58-65.

[31]Lavanya, P., and N. Vijayakumari. Fabrication of Poly (D, L - Alanine)/Minerals Substituted Hydroxyapatite Bio-Composite for Bone Tissue Applications[J]. Materials Discovery, 2018, 11(9): 14-18.

[32]Lazic, Vesna, Ivana Smiciklas, Jelena Markovic, Davor Loncarevic, Jasmina Dostanic, S. Phillip Ahrenkiel, and Jovan M. Nedeljkovic. Antibacterial Ability of Supported Silver Nanoparticles by Functionalized Hydroxyapatite with 5-Aminosalicylic Acid[J]. Vacuum, 2018, 14(8):62-68.

[33]El Rhilassi, A., M. Mourabet, M. Bennani-Ziatni, R. El Hamri, and A. Taitai. Interaction of Some Essential Amino Acids with Synthesized Poorly Crystalline Hydroxyapatite[J]. Journal of Saudi Chemical Society, 2016, 8(6):32-40.

[34]Zhang, Guodong, Jingdi Chen, Shen Yang, Qifeng Yu, Zhili Wang, and Qiqing Zhang. Preparation of Amino-Acid-Regulated Hydroxyapatite Particles by Hydrothermal Method[J]. Materials Letters, 2011, 5(3):72-74.

[35]Katti, D. R., A. Sharma, A. H. Ambre, and K. S. Katti. Molecular Interactions in Biomineralized Hydroxyapatite Amino Acid Modified Nanoclay: In Silico Design of Bone Biomaterials[J]. Mater Sci Eng C Mater Biol Appl, 2015, 20(6):7-17.

[36]Farokhi, M., F. Mottaghitalab, S. Samani, M. A. Shokrgozar, S. C. Kundu, R. L. Reis, Y. Fatahi, and D. L. Kaplan. Silk Fibroin/Hydroxyapatite Composites for Bone Tissue Engineering[J]. Biotechnol Adv, 2018, 3(2):68-91.

[37]Sathiyavimal, Selvam, Seerangaraj Vasantharaj, Felix LewisOscar, Raja Selvaraj, Kathirvel Brindhadevi, and Arivalagan Pugazhendhi. Natural Organic and Inorganic–Hydroxyapatite Biopolymer Composite for Biomedical Applications[J]. Progress in Organic Coatings, 2020, 14(7): 55-62.

[38]Panda, Sikta, Chandan Kumar Biswas, and Subhankar Paul. A Comprehensive Review on the Preparation and Application of Calcium Hydroxyapatite: A Special Focus on Atomic Doping Methods for Bone Tissue Engineering[J]. Ceramics International, 2021, 28(12):22-44.

[39]Sykes, M., E. Kisson, I. Reichert, V. Rose, and R. Ahluwalia. Infected Open Calcaneal Fractures - a Delayed Reconstruction Technique Using Calcium Sulphate and Hydroxyapatite Antibiotic Elucidating Void Filler[J]. J Clin Orthop Trauma, 2020, 4(3):62-66.

[40]Hayashi, Keitaro, and Naohiko Anzai. L-Type Amino Acid Transporter as a Target for Inflammatory Disease and Cancer Immunotherapy[J]. Journal of Pharmacological Sciences, 2021,6(3):125-136.

[41]Yaghoubi, A., and A. Ramazani. Anticancer Dox Delivery System Based on Cnts: Functionalization, Targeting and Novel Technologies[J]. J Control Release, 2020, 16(4):198-224.

[42]Song, Yan, Zheng Qu, Jiangbo Li, Lei Shi, Wancheng Zhao, Henan Wang, Tiedong Sun, Tao Jia, and Yuan Sun. Fabrication of the Biomimetic Dox/Au@Pt Nanoparticles Hybrid Nanostructures for the Combinational Chemo/Photothermal Cancer Therapy[J]. Journal of Alloys and Compounds, 2021, 18(8):35-46.

[43]Zhang, Hui-Fang, Lei Ma, Feng Su, Xiao-Fang Ma, Tao Li, Wu Jian-Zha-Xi, Guo-Hu Zhao, Zi-Mao Wu, Cai-lan Hou, and Hai-jun Yan. Ph and Reduction Dual-Responsive Feather Keratin-Sodium Alginate Nanogels with High Drug Loading Capacity for Tumor-Targeting Dox Delivery[J]. Polymer Testing, 2021, 10(3):47-53.

[44]Li, C., H. Guan, Z. Li, F. Wang, J. Wu, and B. Zhang. Study on Different Particle Sizes of Dox-Loaded Mixed Micelles for Cancer Therapy[J]. Colloids Surf B Biointerfaces, 2020, 19(6):11-13.

[45]Guo, L., X. Zheng, E. Wang, X. Jia, G. Wang, and J. Wen. Irigenin Treatment Alleviates Doxorubicin (Dox)-Induced Cardiotoxicity by Suppressing Apoptosis, Inflammation and Oxidative Stress Via the Increase of Mir-425[J]. Biomed Pharmacother, 2020, 10(15):79-84.

[46]Song, Shuhui, Xinyi Li, Yongsheng Ji, Ruihong Lv, Le Wu, Haohao Wang, Mingzhuo Cao, and Zhigang Xu. Gsh/Ph Dual-Responsive and Ha-Targeting Nano-Carriers for Effective Drug Delivery and Controlled Release[J]. Journal of Drug Delivery Science and Technology, 2021, 4(62):79-86.

[47]Pauloin, A., and C. Thurieau. "The 50 Kda Protein Subunit of Assembly Polypeptide (Ap) Ap-2 Adaptor from Clathrin-Coated Vesicles Is Phosphorylated on Threonine-156 by Ap-1 and a Soluble Ap50 Kinase Which Co-Purifies with the Assembly Polypeptides[J]. The Biochemical journal, 1993, 4(8):9-15.

[48]Demirkiran, H., A. Mohandas, M. Dohi, A. Fuentes, K. Nguyen, and P. Aswath. Bioactivity and Mineralization of Hydroxyapatite with Bioglass as Sintering Aid and Bioceramics with Na3Ca6(PO4)5 and Ca5(PO4)2SiO4 in a Silicate Matrix[J]. Mater Sci Eng C Mater Biol Appl, 2010, 2(2):63-72.

[49]Mahmud, K., A. Mitsionis, T. Vaimakis, N. Kourkoumelis, and C. Trapalis. The Threonine Effect on Calcium Phosphate Preparation from a Solution Containing Ca/P=1.33 Molar Ratio[J]. Ceramics International, 2010, 18(6):93-99.

[50]Ponomareva, N. I., T. D. Poprygina, S. I. Karpov, M. V. Lesovoi, and B. L. Agapov. Microemulsion Method for Producing Hydroxyapatite[J]. Russian Journal of General Chemistry, 2010, 9(5):5-8.

[51]Matsumoto, Takuya, Mohammad Hafiz Uddin, Sang Hyun An, Kazuto Arakawa, Eiji Taguchi, Atsushi Nakahira, and Masayuki Okazaki. Modulation of Nanotube Formation in Apatite Single Crystal Via Organic Molecule Incorporation[J]. Materials Chemistry and Physics, 2011, 4(3):95-99.

[52]Liu, Y., D. B. Raina, S. Sebastian, H. Nagesh, H. Isaksson, J. Engellau, L. Lidgren, and M. Tagil. Sustained and Controlled Delivery of Doxorubicin from an in-Situ Setting Biphasic Hydroxyapatite Carrier for Local Treatment of a Highly Proliferative Human Osteosarcoma[J]. Acta Biomater, 2021, 5(13):55-71.

[53]Sarkar, N., H. Morton, and S. Bose. Effects of Vitamin C on Osteoblast Proliferation and Osteosarcoma Inhibition Using Plasma Coated Hydroxyapatite on Titanium Implants[J]. Surf Coat Technol, 2020, 6(3):59-68.

[54]Y.E, Greish, Bender J.D, Singh A, Nair L.S, Brown P.W, Allcock H.R, and Laurencin C.T. Hydrolysis of Ca-Deficient Hydroxyapatite Precursors in the Presence of Alanine-Functionalized Polyphosphazene Nanofibers[J]. Ceramics International, 2013, 5(1):19-28.

[55]Kaur, G., G. Pickrell, G. Kimsawatde, D. Homa, H. A. Allbee, and N. Sriranganathan. Synthesis, Cytotoxicity, and Hydroxyapatite Formation in 27-Tris-Sbf for Sol-Gel Based CaO-P2O5-SiO2-B2O3-ZnO Bioactive Glasses[J]. Sci Rep, 2014, 3(4):43-52.

[56]Villarreal-Ramirez, E., R. Garduno-Juarez, A. Gericke, and A. Boskey. The Role of Phosphorylation in Dentin Phosphoprotein Peptide Absorption to Hydroxyapatite Surfaces: A Molecular Dynamics Study[J]. Connect Tissue Res 55 Suppl, 2014, 13(1):4-7.

[57]Cho, J. S., J. C. Lee, and S. H. Rhee. Effect of Precursor Concentration and Spray Pyrolysis Temperature Upon Hydroxyapatite Particle Size and Density[J]. J Biomed Mater Res B Appl Biomater, 2016, 4(2):22-30.

[58]Cipreste, Marcelo Fernandes, Michele Rocha de Rezende, Marlon Luiz Hneda, Anderson Maia Peres, Alexandre Alberto Chaves Cotta, Verônica de Carvalho Teixeira, Waldemar Augusto de Almeida Macedo, and Edésia Martins Barros de Sousa. Functionalized-Radiolabeled Hydroxyapatite/Tenorite Nanoparticles as Theranostic Agents for Osteosarcoma[J]. Ceramics International, 2018, 17(15):5-11.

[59]Liu, Guanxiong, Xin Geng, Huan Pang, Xinran Li, Xiaotian Li, Peizhi Zhu, Chao Zhang, and H. R. Bakhsheshi Rad. Deposition of Nanostructured Fluorine-Doped Hydroxyapatite Coating from Aqueous Dispersion by Suspension Plasma Spray[J]. Journal of the American Ceramic Society, 2016, 2(9):899-904.

[60]Begam, Howa, Biswanath Kundu, Abhijit Chanda, and Samit Kumar Nandi. MG63 Osteoblast Cell Response on Zn Doped Hydroxyapatite (Hap) with Various Surface Features[J]. Ceramics International, 2017, 37(4):52-60.

[61]Miculescu, F., A. Maidaniuc, Stefan Ioan Voicu, Vijay Kumar Thakur, G. E. Stan, and L. T. Ciocan. Progress in Hydroxyapatite–Starch Based Sustainable Biomaterials for Biomedical Bone Substitution Applications[J]. ACS Sustainable Chemistry & Engineering, 2017, 10(8):491-512.

中图分类号:

 R318.08    

条码号:

 002000064692    

馆藏号:

 TD10052915    

馆藏位置:

 403    

备注:

 403-西院分馆博硕论文库;203-余家头分馆博硕论文库    

无标题文档

   建议浏览器: 谷歌 火狐 360请用极速模式,双核浏览器请用极速模式