纳米羟基磷灰石及其复合材料作为药物载体的研究进展

卢英; 荀晓伟; 杨志伟; 罗红林; 万怡灶; 左桂福

doi:10.13801/j.cnki.fhclxb.20200814.002

纳米羟基磷灰石及其复合材料作为药物载体的研究进展

doi: 10.13801/j.cnki.fhclxb.20200814.002

卢英^1,,
荀晓伟^1,,
杨志伟^1,,
罗红林^1,,
万怡灶^1,,
左桂福^2, ,

1.
华东交通大学　先进材料研究院江西省纳米生物材料重点实验室，南昌 330013
2.
华北理工大学　材料科学与工程学院，唐山 063210

基金项目: 国家自然科学基金 (51662009；31660264)；江西省教育厅科学技术研究项目(GJJ180348)

详细信息

通讯作者:
左桂福，博士，教授，硕士生导师，研究方向为生物复合材料　E-mail：zuoguifu@163.com

中图分类号: TB332；TQ4460
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- 被引次数: 0
出版历程
- 收稿日期: 2020-06-22
- 录用日期: 2020-08-13
- 网络出版日期: 2020-08-14
- 刊出日期: 2020-12-15

Research progress of nano-hydroxyapatite and its composite materials as drug carriers

LU Ying^1
,,
XUN Xiaowei^1
,,
YANG Zhiwei^1
,,
LUO Honglin^1
,,
WAN Yizao^1
,,
ZUO Guifu^{2
, ,}

1.
Jiangxi Provincial Key Laboratory of Nanometer Biomaterials, Institute of Advanced Materials, East China Jiaotong University, Nanchang 330013, China
2.
School of Materials Science and Engineering, North China University of Science and Technology, Tangshan 063210, China

摘要

摘要: 纳米羟基磷灰石(HAp)具有良好的生物活性和药物吸附性，是一种理想的无机药物载体。本文从生物安全性、抗肿瘤活性和药物吸附性三个方面阐述了纳米HAp的载药特性，探讨了其微观形貌对载药性能的影响，对载药纳米HAp复合材料的分类、制备及载药和释药性能进行了系统综述，旨在为纳米HAp及其复合材料在药物载体领域的应用提供理论基础。
- 纳米羟基磷灰石 /
- 药物载体 /
- 复合材料 /
- 微观形貌 /
- 药物吸附/释放
Abstract: Nano-hydroxyapatite (HAp) is an ideal inorganic drug carrier due to its good biological activity and drug adsorption ability. In this paper, the drug loading performance of nano-HAp was described by three aspects: Biological safety, antitumor activity and drug adsorption. Moreover, the effect of HAp micromorphology on drug-loading performance was also discussed. Furthermore, the classification, preparation, drug loading and drug release of nano-HAp composites were systematic reviewed, which aimed to provide a theoretical basis for application as drug carrier of nano-HAp and its composites.
- nano-hydroxyapatite /
- drug carrier /
- composite materials /
- micro-morphology /
- drug adsorption/release

HTML全文

图 1 羟基磷灰石(HAp)的晶体结构^[28]

Figure 1. Crystal structure of hydroxyapatite (HAp)^[28]

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图 2 载药纳米HAp的几种典型形貌

Figure 2. Several typical morphologies of drug-loaded HAp ((a) Nanorods^[33]; (b) Needle-like shape^[34]; (c) Lamellar^[35]; (d) Hollow microsphere^[36]; (e) Hollow ellipsoidal capsules^[37]; (f) Nanotubes^[38])

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图 3 实心纳米载体(a)和空心多孔纳米载体(b)的载药模型^[47]

Figure 3. Schemes of drug loading for solid nanoparticles (a) and hollow porous nanoparticles (b)^[47]

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图 4 不同形貌的HAp/甲氨蝶呤(MTX)杂化物的制备过程和细胞吞噬示意图^[49]

Figure 4. Schematic diagram of preparation process and cell phagocytosis of HAp/methotrexate (MTX) complexes with different morphologies^[49]

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图 5 层片状HAp(LHAp)/5-FU复合物的制备流程图^[50] (a)和LHAp/DNA的酶解保护和酸解释放示意图^[51] (b)

Figure 5. Preparation flow chart of lamellar HAp (LHAp)/5-FU complex^[50] (a), illustration of DNA protection provided by lamellar HAp and DNA release in acidic conditions^[51] (b)

5-FU—5-fluorouracil

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图 6 HAp@氧化石墨烯(GO)的合成、载药过程、内吞过程和协同治疗癌细胞的示意图^[52]

Figure 6. Schematic illustration of the synthesis of HAp@graphene oxide (GO), the drug loading process, the endocytosis process and the proposed mechanism of synergistic therapy against cancer cells^[52]

DOX—Doxorubicin; NIR—Night-time ozone profile

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图 7 介孔SiO₂纳米颗粒(MSNs)/HAp复合材料的设计、降解和药物储存/释放过程的示意图^[53]

Figure 7. A schematic representation of the design of mesoporous SiO₂ nanoparticle (MSNs)/HAp composites, subsequent degradation and drug storage/release process^[53]

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图 8 CS和CS/LHAp复合水凝胶的反复电刺激质量变化曲线^[57]

Figure 8. Mass changes of composite hydrogels under cyclic on–off switching electrostimulation^[57]

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图 9 DOX@LHAp/聚乳酸羟基乙酸(PLGA)复合材料的药物释放示意图^[60] (a)、DOX@聚丙烯酸(PAA)-介孔羟基磷灰石纳米颗粒(MHAPNs)的制备流程图和细胞内pH响应药物释放示意图^[62] (b)

Figure 9. Schematic diagram of the drug release of DOX@LHAp/polylactic acid (PLGA) composite^[60] (a), schematic illustration of the preparation of DOX@polyacrylic acid (PAA)-mesoporous hydroxyapatite nanoparticles (MHAPNs) and the intracellular pH-responsive drug delivery system^[62] (b)

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图 10 GO/HAp/壳聚糖(CS)/针状HAp纳米晶对顺铂(CDDP)复合材料治疗骨肉瘤的示意图^[65]

Figure 10. Schematic diagram of GO/HAp/chitosan (CS)/cisplatin (CDDP) composite material for the treatment of osteosarcoma^[65]

MG 63 cells—Human osteosarcoma cells

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参考文献(65)

[1]	孙夏囡, 何文, 闫顺璞, 等. 载药纳米羟基磷灰石的研究[J]. 山东轻工业学院学报, 2009, 23(1):44-48. SUN X N, HE W, YAN S P, et al. Study on the drug-loaded nano-hydroxyapatite[J]. Journal of Shandong Institute of Light Industry,2009,23(1):44-48(in Chinese).
[2]	RAUSCHMANNA M A, WICHELHAUS T A, STIRNAL V, et al. Nanocrystalline hydroxyapatite and calcium sulphate as biodegradable composite carrier material for local delivery of antibiotics in bone infections[J]. Biomaterials,2005,26(15):2677-2684. doi: 10.1016/j.biomaterials.2004.06.045
[3]	LEGEROS R Z. Calcium phosphate-based osteoinductive materials[J]. Chemical Reviews,2008,108(11):4742-4753. doi: 10.1021/cr800427g
[4]	陈杰, 王广妮, 严永刚, 等. 可注射nano HA/PAG/CS复合材料的制备与表征[J]. 复合材料学报, 2013, 30(1):96-102. CHEN J, WANG G N, YAN Y G, et al. Preparation and characterization of injectable composite of nano HA/PAG/CS[J]. Acta Materiae Compositae Sinica,2013,30(1):96-102(in Chinese).
[5]	ROUSSLIIE A V. Ultrastructural evidence in vitro of osteoclast-induced degradation of calcium phosphate ceramic by simultaneous resorption and phagocytosis mechanisms[J]. Histology & Histopathology,2001,16(1):37-44.
[6]	LEGEROS R Z. In vitro interactions of bone marrow cells with carbonate and fluoride containing apatites[J]. Key Engineering Materials,2001,192-195:347-350.
[7]	GONDA Y, IOKU K, SHIBATA Y, et al. Stimulatory effect of hydrothermally synthesized biodegradable hydroxyapatite granules on osteogenesis and direct association with osteoclasts[J]. Biomaterials,2009,30(26):4390-4400. doi: 10.1016/j.biomaterials.2009.05.002
[8]	许艳慧, 李四群, 李志安. 纳米羟基磷灰石复合材料的研究-纳米羟基磷灰石的细胞毒性[J]. 实用口腔医学杂志, 2004, 20(2):147-150. doi: 10.3969/j.issn.1001-3733.2004.02.005 XU Y H, LI S Q, LI Z A. Development of nanometer hydroxyapatite complex materials-cytotoxicity test of nano-hydroxyapatite by MTT-assay[J]. Journal of Practical Stomatology,2004,20(2):147-150(in Chinese). doi: 10.3969/j.issn.1001-3733.2004.02.005
[9]	AOKI H, AOKI H, KUTSUNO T, et al. An in vivo study on the reaction of hydroxyapatite-sol injected into blood[J]. Journal of Materials Science: Materials in Medicine,2000,11(2):67-72. doi: 10.1023/A:1008993814033
[10]	MONDAL S, PAL U, DEY A. Natural origin hydroxyapatite scaffold as potential bone tissue engineering substitute[J]. Ceramics International,2016,42(16):18338-18346. doi: 10.1016/j.ceramint.2016.08.165
[11]	HUANG J, BEST S M, BONFIELD W, et al. In vitro assessment of the biological response to nano-sized hydroxyapatite[J]. Journal of Materials Science: Materials in Medicine,2004,15(4):441-445. doi: 10.1023/B:JMSM.0000021117.67205.cf
[12]	PILLIAR R M, FILIAGG M J, WELLS J D, et al. Porous calcium polyphosphate scaffolds for bone substitute applications-in vitro characterization[J]. Biomaterials,2001,22(9):963-972. doi: 10.1016/S0142-9612(00)00261-1
[13]	LI Y, SHI H S, LI G. Current application of hydroxyapatite nanoparticles in tumor field[J]. Journal of Clinical Rehabilitative Tissue Engineering Research,2008,12(32):6393-6396.
[14]	王志新, 刘莹, 孔祥波, 等. 纳米羟基磷灰石对人源性泌尿系肿瘤细胞增殖的影响[J]. 中国老年学杂志, 2007, 27(23):2276-2277. doi: 10.3969/j.issn.1005-9202.2007.23.005 WANG Z X, LIU Y, KONG X B, et al. The effect of nano-hydroxyapatite on the proliferation of human urinary tumor cells[J]. Chinese Journal of Gerontology,2007,27(23):2276-2277(in Chinese). doi: 10.3969/j.issn.1005-9202.2007.23.005
[15]	张士成, 李世普, 陈芳. 磷灰石超微粉对癌细胞作用的初步研究[J]. 武汉工业大学学报, 1996, 18(1):5-8. ZHANG S C, LI S P, CHENG F. Studies on effects of apatite ultrafinepowder on cancer cells[J]. Journal of Wuhan University of Technology,1996,18(1):5-8(in Chinese).
[16]	CHU S H, FENG D F, MA Y B, et al. Hydroxyapatite nanoparticles inhibit the growth of human glioma cells in vitro and in vivo[J]. International Journal of Nanomedicine,2012,7:3659-3666.
[17]	ZHANG K, ZHOU Y, XIAO C, et al. Application of hydroxyapatite nanoparticles in tumor-associated bone segmental defect[J]. Science Advances,2019,5(8):1-16.
[18]	冯凌云, 阎玉华, 陈闻杰, 等. 羟基磷灰石溶胶对W-256癌肉瘤细胞内钙离子浓度及细胞形态结构的影响[J]. 中国生物医学工程学报, 1998, 17(4):374-377. FENG L Y, YAN Y H, CHEN W J, et al. Effect of HAp-sol on Ca²⁺ concentration of W-256 sarcoma cells and morphology of cells[J]. Chinese Journal of Biomedical Engineering,1998,17(4):374-377(in Chinese).
[19]	张建平, 夏清华. 羟基磷灰石超微粉对肿瘤细胞系Walker256的DNA损伤[J]. 实用癌症杂志, 1997, 12(4):245-247. ZHANG J P, XIA Q H. The role of hydroxyapatite ultrafinepower in DNA damage of the tumer cell line Walker256[J]. The Practical Journal of Cancer,1997,12(4):245-247(in Chinese).
[20]	CHEN J, LI S P. The influence of nano-apatite on c-myc and p53 gene in the hepatocellular carcinoma[J]. Journal of Wuhan University of Technology-Materials Science,2005,20(2):57-59. doi: 10.1007/BF02838489
[21]	夏清华, 陈道林, 林华, 等. HASM对W-256细胞系DNA含量及细胞周期的影响[J]. 武汉工业大学学报, 1999, 21(2):5-6. XIA Q H, CHEN D L, LIN H, et al. Effects of hydroxyapatite supermicromist on DNA content and cell cycle of W-256 sarcoma cell[J]. Journal of Wuhan University of Technology,1999,21(2):5-6(in Chinese).
[22]	曹献英, 李世普, 闫玉华, 等. 纳米羟基磷灰石的表征及其对肝癌抑制作用的研究[J]. 硅酸盐通报, 2015, 22(4):21-24. CHAO X Y, LI S P, YAN Y H, et al. Study on characterizition of nano-HAP and its inhibition on human hepatocelluar carcinoma cell lins[J]. Bulletin of The Chinese Ceramic Society,2015,22(4):21-24(in Chinese).
[23]	陈筠, 曹献英, 韩颖超, 等. 纳米磷灰石对肝癌癌基因表达的影响[J]. 武汉理工大学学报, 2005, 27(9):29-31. doi: 10.3321/j.issn:1671-4431.2005.09.010 CHEN J, CAO X Y, HAN Y C, et al. Affection of nano-apatite on the expression of the oncogene and anti-oncogene in the hepatocellular carcinoma cells[J]. Journal of Wuhan University of Technology,2005,27(9):29-31(in Chinese). doi: 10.3321/j.issn:1671-4431.2005.09.010
[24]	LI S P. The effect of nano-apatite on the expression of telomerase gene of human hepatocellular carcinoma cells[J]. Journal of Wuhan University of Technology,2004,20(12):315-317.
[25]	JIN J, ZUO G F, XIONG G Y, et al. The inhibition of lamellar hydroxyapatite and lamellar magnetic hydroxyapatite on the migration and adhesion of breast cancer cells[J]. Journal of Materials Science: Materials in Medicine,2014,25(4):1025-1031. doi: 10.1007/s10856-013-5126-8
[26]	赵欣, 王德平. 纳米羟基磷灰石作为药物载体材料的研究进展[J]. 材料导报, 2010, 24(12):116-120. ZHAO X, WANG D P. The research development of nano-hydroxyapatite as a drug carrier[J]. Materials Reports,2010,24(12):116-120(in Chinese).
[27]	KAY M I, YOUNG R A, POSNER A S. Crystal structure of hydroxyapatite[J]. Nature,1964,204(4963):1050-1052. doi: 10.1038/2041050a0
[28]	邹雪艳, 赵彦保, 张治军. 纳米羟基磷灰石的合成方法研究进展[J]. 化学研究, 2019, 20(4):404-410. ZOU X Y, ZHAO Y B, ZHANG Z Z. Progress in the synthesis method of hydroxyapatite[J]. Chemical Research,2019,20(4):404-410(in Chinese).
[29]	陈庆榆, 朱融融, 张蕤, 等. 纳米羟基磷灰石对两种药物的载药性能研究[J]. 复旦学报, 2009, 48(3):386-390. CHEN Q Y, ZHU R R, ZHANG R, et al. Preparation and characterization of nano-hydroxyapatite as carrier of two drugs[J]. Journal of Fudan University,2009,48(3):386-390(in Chinese).
[30]	ZHOU H L, WU T, DONG X L, et al. Adsorption mechanism of BMP-7 on hydroxyapatite (001) surfaces[J]. Biochemical and Biophysical Research Communications,2007,361(1):91-96. doi: 10.1016/j.bbrc.2007.06.169
[31]	PAN H H, TAO X H, XU H R, et al. Adsorption processes of Gly and Glu amino acids on hydroxyapatite surfaces at the atomic level[J]. Langmuir,2007,23(17):8972-8981. doi: 10.1021/la700567r
[32]	SZCZEŚ A, HOLYSZ L, CHIBOWSKI E. Synthesis of hydroxyapatite for biomedical applications[J]. Advances in Colloid and Interface Science,2017,249:321-330. doi: 10.1016/j.cis.2017.04.007
[33]	ZHANG C M, LI C X, HUANG S S, et al. Self-activated luminescent and mesoporous strontium hydroxyapatite nanorods for drug delivery[J]. Biomaterials,2010,31(12):3374-3383. doi: 10.1016/j.biomaterials.2010.01.044
[34]	SANTOS C, TURIEL S, GOMES P S, et al. Vascular biosafety of commercial hydroxyapatite particles: Discrepancy between blood compatibility assays and endothelial cell behavior[J]. Journal of Nanobiotechnology,2018,16(1):27. doi: 10.1186/s12951-018-0357-y
[35]	WAN Y Z, WU C Q, ZUO G F, et al. Controlled template synthesis of lamellar hydroxyapatite nanoplates as a potential carrier for gene delivery[J]. Materials Chemistry and Physics,2015,156:238-246. doi: 10.1016/j.matchemphys.2015.03.011
[36]	ZHAO Q, ZHANG D Q, SUN R X, et al. Adsorption behavior of drugs on hydroxyapatite with different morphologies: A combined experimental and molecular dynamics simulation study[J]. Ceramics International,2019,45(15):19522-19527. doi: 10.1016/j.ceramint.2019.06.068
[37]	MA M Y, ZHU Y J, LI L, et al. Nanostructured porous hollow ellipsoidal capsules of hydroxyapatite and calcium silicate: preparation and application in drug delivery[J]. Journal of Materials Chemistry,2008,18(23):2722-2727. doi: 10.1039/b800389k
[38]	GUO X K, YU L, CHEN L H, et al. Organoamine-assisted biomimetic synthesis of faceted hexagonal hydroxyapatite nanotubes with prominent stimulation activity for osteoblast proliferation[J]. Journal of Materials Chemistry B,2014,2(13):1760-1763. doi: 10.1039/C3TB21652G
[39]	HAIDER A, HAIDER S, HAN S S, et al. Recent advances in the synthesis, functionalization and biomedical applications of hydroxyapatite: A review[J]. RSC Advances,2017,7(13):7442-7458. doi: 10.1039/C6RA26124H
[40]	MONDAL S, DOROZHKIN S V, PAL U. Recent progress on fabrication and drug delivery applications of nanostructured hydroxyapatite[J]. Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology,2018,10(4):1-32.
[41]	李宾杰, 姚素梅, 李淑莲, 等. 纳米羟基磷灰石的制备及在生物医学上的应用研究进展[J]. 化学研究, 2010, 21(5):90-96. doi: 10.3969/j.issn.1008-1011.2010.05.024 LI B J, YAO S M, LI S L, et al. Research progress in preparation of nanoscale hydroxyapatite and its application in biomedicine field[J]. Chemical Research,2010,21(5):90-96(in Chinese). doi: 10.3969/j.issn.1008-1011.2010.05.024
[42]	赵宏霞. 羟基磷灰石微结构调控的研究进展[J]. 功能材料, 2017, 1(48):1047-1055. ZHAO H X. Research progress of microstructure regulation for hydroxyapatite[J]. Functional Materials,2017,1(48):1047-1055(in Chinese).
[43]	XU S Y, LONG J D, SIM L, et al. RF plasma sputtering deposition of hydroxyapatite bioceramics: Synthesis, performance, and biocompatibility[J]. Plasma Processes & Polymers,2005,2(5):373-390.
[44]	ZHAO X, NG S, HENG B C, et al. Cytotoxicity of hydroxyapatite nanoparticles is shape and cell dependent[J]. Archives of Toxicology,2013,87(6):1037-1052. doi: 10.1007/s00204-012-0827-1
[45]	GUPTA A S. Role of particle size, shape, and stiffness in design of intravascular drug delivery systems: Insights from computations, experiments, and nature[J]. Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology,2015,8(2):255-270.
[46]	MANIYA N H, PATEL S R, MURTHY Z V P. Electrochemical preparation of microstructured porous silicon layers for drug delivery applications[J]. Superlattices & Microstructures,2013,55:144-150.
[47]	刘安琪, 陈建峰, 李雪光, 等. 空心多孔纳米载体负载药物的药量分布研究[J]. 高校化学工程学报, 2007, 21(5):832-837. doi: 10.3321/j.issn:1003-9015.2007.05.018 LIU A Q, CHEN J F, LI X G, et al. Study of drug loading distribution of porous hollow nano-carriers[J]. Journal of Chemical Engineering of Chinese Universities,2007,21(5):832-837(in Chinese). doi: 10.3321/j.issn:1003-9015.2007.05.018
[48]	PALAZZO B, IAFISCO M, LAFORGIA M, et al. Biomimetic hydroxyapatite-drug nanocrystals as potential bone substitutes with antitumor drug delivery properties[J]. Advanced Functional Materials,2007,17(13):2180-2188. doi: 10.1002/adfm.200600361
[49]	SUN H N, LIU S S, ZENG X F, et al. Morphology effect of nano-hydroxyapatite as a drug carrier of methotrexate[J]. Journal of Materials Science Materials in Medicine,2017,28(10):158. doi: 10.1007/s10856-017-5978-4
[50]	LUO H L, JI D H, LI C Z, et al. Layered nanohydroxyapatite as a novel nanocarrier for controlled delivery of 5-fluorouracil[J]. International Journal of Pharmaceutics,2016,513(1-2):17-25. doi: 10.1016/j.ijpharm.2016.09.004
[51]	ZUO G F, WAN Y Z, MENG X G, et al. Synthesis and characterization of a lamellar hydroxyapatite/DNA nanohybrid[J]. Materials Chemistry and Physics,2011,126(3):470-475. doi: 10.1016/j.matchemphys.2010.12.060
[52]	SANG R, CHEN M, YANG Y Y, et al. HAp@GO drug delivery vehicle with dual-stimuli-triggered drug release property and efficient synergistic therapy function against cancer[J]. Journal of Biomedical Materials Research Part A,2019,107(10):2296-2309. doi: 10.1002/jbm.a.36738
[53]	HAO X H, HU X X, ZHANG C M, et al. Hybrid mesoporous silica-based drug carrier nanostructures with improved degradability by hydroxyapatite[J]. ACS Nano,2015,9(10):9614-9625. doi: 10.1021/nn507485j
[54]	胡龙驹, 杨建东. 纳米羟基磷灰石人工骨复合材料载药研究进展[J]. 中国骨与关节损伤杂志, 2013, 28(3):297-299. doi: 10.7531/j.issn.1672-9935.2013.03.053 HU L J, YANG J D. Research progress on drug loading of nano-hydroxyapatite artificial bone composites[J]. Chinese Journal of Bone and Joint Injury,2013,28(3):297-299(in Chinese). doi: 10.7531/j.issn.1672-9935.2013.03.053
[55]	ZOU Q, LI Y B, ZHANG L, et al. Antibiotic delivery system using nano-hydroxyapatite/chitosan bone cement consisting of berberine[J]. Journal of Biomedical Materials Research Part A,2009,89(4):1108-1117.
[56]	DING Z Z, FAN Z H, HUANG X W, et al. Bioactive natural protein-hydroxyapatite nanocarriers for optimizing osteogenic differentiation of mesenchymal stem cells[J]. Journal of Materials Chemistry B,2016,40(20):3555-3561.
[57]	ZUO G F, WAN Y Z, LIU Z J, et al. Preparation and characterisation of laminated hydroxyapatite/chitosan compo-site hydrogels[J]. Plastics, Rubber and Composites,2013,43(2):71-75.
[58]	MA X Y, DONG X L, ZHANG C Y, et al. Polyglutamic acid-coordinated assembly of hydroxyapatite nanoparticles for synergistic tumor-specific therapy[J]. Nanoscale,2019,11(32):15312-15325. doi: 10.1039/C9NR03176F
[59]	GUO B L, MA P X. Synthetic biodegradable functional polymers for tissue engineering: A brief review[J]. Science China-Chemistry,2014,57(4):490-500. doi: 10.1007/s11426-014-5086-y
[60]	LUO H L, ZHANG Y, YANG Z W, et al. Encapsulating doxorubicin-intercalated lamellar nanohydroxyapatite into PLGA nanofibers for sustained drug release[J]. Current Applied Physics,2019,19(11):1204-1210. doi: 10.1016/j.cap.2019.08.003
[61]	TAI I C, FU Y C, WANG C K, et al. Local delivery of controlled-release simvastatin/PLGA/HAp microspheres enhances bone repair[J]. International Journal of Nanomedicine,2013,8:3895-3904.
[62]	LI D L, XIN H, WU Y D, et al. Preparation of pH-responsive mesoporous hydroxyapatite nanoparticles for intracellular controlled release of an anticancer drug[J]. Biomaterials Science,2016,4(2):272-280. doi: 10.1039/C5BM00228A
[63]	牛旭锋, 冯庆玲, 王明波, 等. 微囊化壳聚糖/纳米羟基磷灰石/胶原/聚乳酸复合材料[J]. 复合材料学报, 2009, 26(2):143-148. doi: 10.3321/j.issn:1000-3851.2009.02.025 NIU X F, FENG Q L, WANG M B, et al. Chitosan microspheres/nano-hydroxyapatite/collagen/polylactide composite[J]. Acta Materiae Compositae Sinica,2009,26(2):143-148(in Chinese). doi: 10.3321/j.issn:1000-3851.2009.02.025
[64]	SUMATHRA M, MUNUSAMY M A, ALARFAJ A A, et al. Osteoblast response to vitamin D3 loaded cellulose enriched hydroxyapatite mesoporous silica nanoparticles compo-site[J]. Biomedicine & Pharmacotherapy,2018,103:858-868.
[65]	SUMATHRA M, SADASIVUNI K K, KUMAR S S, et al. Cisplatin-loaded graphene oxide/chitosan/hydroxyapatite composite as a promising tool for osteosarcoma-affected bone regeneration[J]. ACS Omega,2018,3(11):14620-14633. doi: 10.1021/acsomega.8b02090