Optimization of the Formulation of Fe3O4 Nanoparticles by Box-Behnken Response Surface Method and Its Drug Release Mechanism In Vitro
ZHAO Qing1,2,3, CHEN Si-ying1,2, WU Dan2,3, LIU Fan2,3, WANG Ai-min1,4, LIU Ting1,2, YANG Chang1,2,5*
1. State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550004, China; 2. Guizhou Provincial Key Laboratory of Pharmaceutics, Guizhou Medical University, Guiyang 550004, China; 3. School of Pharmacy, Guizhou Medical University, Guiyang 550025, China; 4. Engineering Research Center for the Development and Application of Ethnic Medicine and TCM (Ministry of Education), Guizhou Medical University, Guiyang 550004, China; 5. National Engineering Technology Research Center of Miao��s Medicine, Guiyang 550004, China)
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.
����, ��˼ӱ, �ⵢ, ����, ������, ��ͤ, �. ����Box-BehnkenЧӦ�淨�Ż�Fe3O4�������Ĵ�������������ҩ�����о�[J]. �й�ҩѧ��־, 2019, 54(9): 711-719.
ZHAO Qing, CHEN Si-ying, WU Dan, LIU Fan, WANG Ai-min, LIU Ting, YANG Chang. Optimization of the Formulation of Fe3O4 Nanoparticles by Box-Behnken Response Surface Method and Its Drug Release Mechanism In Vitro. Chinese Pharmaceutical Journal, 2019, 54(9): 711-719.
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(������չ), 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(��������), 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(����ѧ��), 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(ҩѧѧ��), 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(Ӧ�û���), 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(�㶫����), 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(�й��ִ�Ӧ��ҩѧ), 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(������ҽ��ҩ��־), 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(�й���ҩ��־), 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(�й�ҩʦ), 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(ҽҩ����), 2018, 37(2):212-216.
[18]
DING X, CHEN G J.Chemotherapy resistance of 5-fluorouracil:research advances . J Int Pharm Res(����ҩѧ�о���־), 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(�й�ҽҩ����), 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(ɽ��ҽ�ƴ�ѧѧ��), 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(������ҽҩ��ѧѧ��), 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(�й�ҩѧ��־), 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(�й�ʵ�鷽��ѧ��־), 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 (��) complex and determination of Fe (��). Chin J Exp Tradit Med Form(�й�ʵ�鷽��ѧ��־), 2010, 16(7):47-49.
[26]
LIU S S, HO P C. Formulation optimization of scutellarin-loaded HP-��-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(��ѧ�о�),2012,23(1):24-28.
2019, Vol. 54 
