目的 对自制的聚乙二醇(PEG)修饰的四氧化三铁(Fe3O4)纳米颗粒进行处方优化,并对其体外释药机制进行研究。方法 采用Box-Behnken效应面法优化Fe3O4纳米颗粒的处方;通过测定不同时间点Fe3O4纳米颗粒的粒径考察其常温下物理化学稳定性;利用超声搅拌法制备分别负载盐酸多柔比星、灯盏乙素、氟尿嘧啶3种不同类型药物的Fe3O4纳米颗粒,并采用透析法对Fe3O4纳米颗粒的释药能力进行研究,再应用不同的数学模型拟合释药数据,阐释其释药机制;最后在不同温度下考察Fe3O4纳米颗粒的释药能力,说明其光热效应对药物释放的影响。结果 常温下Fe3O4纳米颗粒粒径在20~30 nm之间;Fe3O4纳米颗粒负载水溶性药物氟尿嘧啶时与5种模型的拟合度均不高,负载盐酸多柔比星时与Higuchi方程的拟合度较高,而负载灯盏乙素时与零级方程和Hixson-Crowell方程的拟合度均达到0.996 7,且用于机制验证的Ritger-Peppas方程指出,Fe3O4纳米颗粒装载亲水性药物时释药机制为简单的扩散,而装载疏水性药物时主要通过溶蚀机制进行零级控制释放;随着温度升高,Fe3O4纳米颗粒的释药能力增加。结论 疏水性药物可通过超声搅拌的方法载入Fe3O4纳米颗粒中以提高其生物相容性,为难溶性药物的新剂型研究开发奠定了实验基础。
Abstract
OBJECTIVE To optimize the formulation of Fe3O4 nanoparticles modified with polyethylene glycol (PEG)through Box-Behnken response surface method.To investigate its release properties in vitro to provide references for the study of drug delivery system. METHODS Firstly, the formulationof Fe3O4 nanoparticles was optimized by Box-Behnken response surface method. Secondly, the physical and chemical stabilities of Fe3O4 nanoparticles were determined at different stages. Next, doxorubicin hydrochloride, scutellarin and 5-fluorouracil were respectively loaded into Fe3O4 nanoparticles by ultrasonic stirring method and the drug release ability of Fe3O4 nanoparticles was studied by dialysis method. Finally, different mathematical models were applied to fit the release data to explain the release mechanism, and the release ability of Fe3O4 nanoparticles was investigated at different temperatures to clarify the effect of photothermal effect on drug release. RESULTS The particle size of Fe3O4 nanoparticles was from 20 to 30 nm at room temperature. Fe3O4 nanoparticles loading with water-soluble drugs 5-fluorouracil was incompatible with the five models. However, when doxorubicin hydrochloride was loaded, its release fitted well with the Higuchi equation. And both zero-order equation and the Hixson-Crowell equation can match well with such Fe3O4 nanoparticles loading with scutellarin. Finally, it can be clarified with mechanism-verified Ritger-Peppas equation that the simple diffusion motivated the drug release of Fe3O4 nanoparticles loaded with hydrophilic drugs, and the Zero dissolution release mechanism worked when loaded with hydrophobic drugs.As the temperature increases, the release ability of Fe3O4 nanoparticles was increases. CONCLUSION Hydrophobic drugs can be loaded with SCU in the Fe3O4 nanoparticles by ultrasonic stirring method to improve the biocompatibility of the drugs, which provide some experimental foundation for the research and development of new formulations of poorly soluble drugs.
关键词
Fe3O4纳米颗粒 /
聚乙二醇 /
Box-Behnken效应面法 /
体外释药 /
光热控释
{{custom_keyword}} /
Key words
Fe3O4 nanoparticles /
polyethylene glycol /
Box-Behnken response surface method /
in vitro release /
photothermal controlled release
{{custom_keyword}} /
中图分类号：
R944
{{custom_clc.code}}
({{custom_clc.text}})
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
[1] ZHAN H, BIAN Y, YUAN Q, et al. Preparation and potential applications of super paramagnetic nano-Fe3O4 . Processes, 2018, 6(4):33-35.
[2] L F, LIAO J J, LIU Y, et al. Advance in preparation of Fe3O4 nanoparticles by solvothermal method. Chem Ind Eng Prog(化工进展), 2017, 36(B11):326-331.
[3] WANG G, ZHAO D, LI N, et al. Drug-loaded poly (e-caprolactone)/Fe3O4, composite microspheres for magnetic resonance imaging and controlled drug delivery. J Magn Magn Mater, 2018, 456(15):316-323.
[4] YAN W, GUO J J, XIANG C Y, et al. Research on magnetic iron oxide nanoparticles for theranostics . J Hubei Univ(Nat Sci), 2017, 39(3):317-322.
[5] MA X F. Research progress of nano materials Fe3O4 in biomedical field . Contemp Chem Ind(当代化工), 2016, 45(8):1950-1952.
[6] HU P, CHANG T, CHEN Z Y, et al. Surface modification and application in biomedicine and environmental protection of magnetic Fe3O4 nanoparticle . J Chem Ind Eng(化工学报), 2017, 68(7):2641-2652.
[7] ADIMOOLAM M G, AMREDDY N, NALAM M R, et al. A simple approach to design chitosan functionalized Fe3O4 nanoparticles for pH responsive delivery of doxorubicin for cancer therapy. J Magn Magn Mater, 2018, 445(15):199-207.
[8] NIGAM S, BAFIEK K C, BAHADUR D J, et al. Development of citrate-stabilized Fe3O4 nanoparticles: conjugation and release of doxorubicin for therapeutic applications. J Magn Magn Mater, 2011, 323 (2):237-243.
[9] SHEN S, WU L, WANG C R, et al. Preparation and in vitro evaluation of doxorubicin-loaded magnetic iron oxide nanoparticles . Acta Pharm Sin(药学学报), 2013, 48 (12):1844-1849.
[10] HU J, DEHSORKHI A, ALJAMAL W T, et al. Studies on the photothermal effect of PEGylated Fe3O4 nanoparticles . Nanosci Nanotechnol Lett, 2017, 9(4):556-561.
[11] LI N, NAN Y F, ZHANG X L, et al. Fluorescence analysis of doxorubicin hydrochloride and its injection . Appl Chem Ind(应用化工), 2015, 44(1):178-180.
[12] WANG Y M, ZHAO J L, QIN L H. Study on vivo and in vitro drug release properties of DOX loaded erythrocyte delivery system . Guangdong Chem Ind(广东化工), 2018, 45(5):38-38.
[13] DAI D B, XU J Z, YOU W T, et al. Preparation of doxorubicin-loaded PLA nanoparticles and study their pharmacokineties in rats. Chin J Mod Appl Pharm(中国现代应用药学), 2017, 34(8):1127-1132.
[14] ZHANG H X, YANG H J, BAO G F, et al. Advances in research on main pharmacodynamics of breviscapine . Yunnan J Tradit Chin Med(云南中医中药杂志), 2016, 37(2):75-78.
[15] SHI S L, XU L Y, MAO Z K, et al. Study on physicochemical properties and influence factors on stability of breviscapine . China J Chin Mater Med(中国中药杂志), 2009, 34(7):843-847.
[16] LIU R T, PAN X D, LUO X H, et al. Preparation and charaeterization of seutellarin nanosuspension . China Pharm(中国药师), 2017, 20(1):42-45.
[17] LIU J M, XU Z J, YANG Y X, et al. Preparation of seutellarin liposomes and its pharmacokinetics in rats. Her Med(医药导报), 2018, 37(2):212-216.
[18] DING X, CHEN G J.Chemotherapy resistance of 5-fluorouracil:research advances . J Int Pharm Res(国际药学研究杂志), 2017, 44(6):491-494.
[19] YE S F, CHEN Y, SHOU F, et al. Clinical effect of 5-fluorouracil and gemcitabine combined with concur.rent radiotherapy in the treatment of locally advanced pancreatic carcinoma . China Med Her(中国医药导报), 2017, 14(14):84-87.
[20] CUI L J, HUANG J, LI X H, et al. Preparation and quality control of 5-fluorouracil-polylactic acid sustained release tablet . J Shanxi Med Univ(山西医科大学学报), 2017,48(10):1023-1029.
[21] CHEN K, GUO W J, ZHANG L, et al. Research of preparation and in vitro release of 5-fluorojuracil liquid suppositorie . J Hubei Univ Chin Med(湖北中医药大学学报), 2018, 20(1):49-52.
[22] XIE Y B, YUE P F, DAN Q X, et al. Research progress of in vitro release evaluation methods for nano preparation . Chin Pharm J(中国药学杂志), 2016, 51(11):861-866.
[23] QI N, LIU G, LIAO Y, et al. Preparation and in vitro release behavior investigation of ursolic acid liposome . Chin J Exp Tradit Med Form(中国实验方剂学杂志), 2013, 19(2):28-31.
[24] D′SOUZA S. A review of in vitro drug release test methods for nano-sized dosage forms. Adv Pharm, 2014, 2014(11):1-12.
[25] LI Y X, YOU Z H, ZHU Y X. Synthesis of Lily Polysaccharide-Fe (Ⅲ) complex and determination of Fe (Ⅲ). Chin J Exp Tradit Med Form(中国实验方剂学杂志), 2010, 16(7):47-49.
[26] LIU S S, HO P C. Formulation optimization of scutellarin-loaded HP-β-CD/chitosan nanoparticles using response surface methodology with Box-Behnken design. Asian J Pharm Sci, 2017, 12 (4):378-385.
[27] WU D D, CHEN Z, LONG S H, et al. Release behavior of 5-fluorouracil in pH-sensitive molecular sieve drug release carrier. Chem Res(化学研究),2012,23(1):24-28.
{{custom_fnGroup.title_cn}}
脚注
{{custom_fn.content}}
基金
国家自然科学基金项目资助(81860323,81760699);
贵州省科技厅-贵州医科大学科学技术联合基金项目资助;
贵州省科学技术厅人才团队项目资助
{{custom_fund}}
PDF(1969 KB)
