Preparation and Characterization of Thermo-sensitive N-Acetyl Glycol Chitosan Hydrogel for Sustained Drug Release†

doi:10.7503/cjcu20160513

Abstract

Abstract:

A novel thermo-sensitive polymer N-acetyl glycol chitosan(NAGC) by N-acetylation of glycol chitosan with acetic anhydride was prepared. The chemical structure, thermo-sensitive property, morphology and in vitro drug release properties of NAGC hydrogel were investigated by means of ¹H NMR, FTIR, tube inverting method, SEM and UV-Vis spectroscopy. The results show that the degree of acetylation(DA) of NAGC is increased along with the increase of the feed molar ratio of acetic anhydride to glycol chitosan and reaction time. NAGC hydrogel shows reversible thermo-sensitive sol-gel transition behavior, and the sol-gel transition temperature is well controlled from 25 ℃ to 37 ℃ by controlling the DA and polymer concentration. NAGC hydrogels show macroporous structure with the pore size of 1—40 μm. The pores are well-interconnected to each other and the pore size could be controlled by changing the DA and concentration of NAGC. NAGC hydrogel(DA=89.90%, 5%—7%, mass fraction) shows sustained release behavior for anticancer drug gemcitabine, and the release time could be controlled from 3 d to 5 d. NAGC shows great promise for various biomedical applications, such as drug delivery and tissue engineering.

Key words: Glycol chitosan, N-Acetyl glycol chitosan, Thermo-sensitive hydrogel, Drug release carrier

CLC Number:

O636

TrendMD:

LI Zhengzheng, XU Ziyang, GAO Liuyi, ZENG Wei, ZHAO Linlin. Preparation and Characterization of Thermo-sensitive N-Acetyl Glycol Chitosan Hydrogel for Sustained Drug Release^†[J]. Chem. J. Chinese Universities, 2016, 37(12): 2299.

Figures/Tables 11

Scheme 1 Synthetic route of N-acetyl glycol chitosan

Table 1 Degree of acetylation of N-acetyl glycol chitosan with different molar ratiosa

Sample	Molar ratio^b	DA(%)
NAGC 1	5∶1	72.90
NAGC 2	10∶1	73.42
NAGC 3	20∶1	79.37
NAGC 4	30∶1	87.23

Table 2 Degree of acetylation of N-acetyl glycol chitosan with different reaction time

Sample^*	Reaction time/h	DA(%)
NAGC 5	2	75.62
NAGC 6	4	83.88
NAGC 7	8	87.23
NAGC 8	12	89.90

Fig.1 1H NMR spectra of glycol chitosan and NAGC with different molar ratios(A) and different reaction time(B)

Fig.2 FTIR spectra of glycol chitosan and NAGC prepared with different mole ratios(A) and different reaction time(B)^ (A) a. Glycol chitosan; b. NAGC 1; c. NAGC 2; d. NAGC 3; e. NAGC 4.(B) a. glycol chitosan; b. NAGC 5; c. NAGC 6; d. NAGC 7; e. NAGC 8.

Fig.3 Sol-gel transition phase diagram of NAGC measured by the tube inverting method^Insets are the maps of sol and gel.

Scheme 2 Mechanism of thermo-sensitive sol-gel transition of NAGC

Fig.4 SEM images of surface morphology of lyophilized NAGC hydrogel with different DA and concentration^(A) NAGC 6(5%); (B) NAGC 7(5%); (C) NAGC 8(5%); (D) NAGC 6(7%); (E) NAGC 7(7%); (F) NAGC 8(7%).

Fig.5 Drug release curves of gemcitabine loaded NAGC[5%(a) and 7%(b)] hydrogel

Table 3 Fitting equation of the drug release behavior of NAGC hydrogel(DA=89.90%, 5%)

Time/d	Model	Equation	A	c	R²
0—1	First-order release	ln(1-R)=At+c	-2.1953	-0.1267	0.9895
1—3	Ritger-Peppas	lnR=Alnt+c	0.105	-0.1493	0.9657
3—8	Higuchi	R=At^1/2+c	0.0005	0.9625	0.9988

Table 4 Fitting equation of the drug release behavior of NAGC hydrogel(DA=89.90%, 7%)

Time/d	Model	Equation	A	c	R²
0—1	First-order release	ln(1-R)=At+c	0.105	-0.143	0.9844
1—5	Ritger-Peppas	lnR=Alnt+c	4.5189	1.7202	0.9705
5—8	Higuchi	R=At^1/2+c	0.0078	0.9018	0.9634

References 25

[1]	Sadia A., Shaista K., Atif I., Irtaza J., Tahir J., Muhammad M. A., Muhammad I. S., Abdul G., Int. J. Biol. Macromolec., 2015, 80, 240—245
[2]	Sivashanmugam A., Arun Kumar R., Vishnu Priya M., Nair S. V., Jayakumar R., Eur. Polym. J., 2015, 72, 543—565
[3]	Cong T. H., Nguyen M. K., Lee D. S., Acta Biomater., 2011, 7, 3123—3130
[4]	Nguyen Q. V., Dai P. H., Park J. H., Lee D. S., Eur. Polym. J., 2015, 72, 602—619
[5]	Sytze J. B., Kristel W. M. B., Pieter J. D., Jan F., Tina V., Wim E. H., J. Control. Release., 2014, 190, 254—273
[6]	Niels M. B. S., Emilia B., Mathew P., Todd H., Acta Biomater., 2014, 10, 4143—4155
[7]	Paul Z. E., Gary W. L., Hua W., Michael C. J., Philip J. H., Suzie H. P. J. Control. Release., 2015, 208, 76—84
[8]	Lin C., Zhao P., Li F., Guo F., Li Z., Wen X.,Mater. Sci. Eng. C, 2010, 30, 1236—1244
[9]	Yu L., Ding J. D., Chem. Soc. Rev., 2008, 37(7), 1473—1481
[10]	Ni P. Y., Ding Q. X., Fan M., Liao J. F., Qian Z. Y., Luo J. C., Li X. Q., Feng L., Yang Z. M., Wei Y. Q., Biomaterials, 2014, 35, 236—248
[11]	Sarah P. H., Robert L., Gerald R. F., Daniel S. K., Biomaterials, 2010, 31, 1444—1452
[12]	Li L., Wang N., Jin X., Deng R., Nie S. H., Sun L., Wu Q. J., Wei Y. Q., Gong C. Y., Biomaterials, 2014, 35, 3903—3917
[13]	Xie B. B., Jin L., Luo Z. C., Yu J., Shi S., Zhang Z. L., Shen M. X., Chen H., Li X. Y., Song Z. M., Int. J. Pharm., 2015, 490, 375—383
[14]	Yannic B. S., Robert G., Olivier J., Eur. J. Pharm. Biopharm., 2008, 68, 19—25
[15]	Chen J. P., Cheng T. H., Polymer, 2009, 50, 107—116
[16]	Elie Z., Shreya R., Robert R. G., Khalil N. B., Biomaterials, 2012, 33, 4810—4817
[17]	Elias A., Marion M., Sophie L., Carbohydr. Polym., 2015, 130, 87—96
[18]	Cao L. P., Cao B., Lu C. J., Wang G. W., Yu L., Ding J. D., J. Mater. Chem. B, 2015, 3, 1268—1280
[19]	Songkroh T., Xie H. G., Yu W. T., Lv G. J., Liu X. D., Wang L., Sun G. W., Xu X. X., Ma X. J., Sci. Bull., 2015, 60(2), 235—240
[20]	Monier M., Ayad D. M., Wei Y., Sarhan A. A., Biochem. Eng. J., 2010, 51, 140—146
[21]	Yu J. M., Li Y. J., Wang C. R., Yin Y. S. , Qiu L. Y., Jin Y., Journal of Chinese Pharmaceutical Sciences, 2010, 45, 277—282
	(余敬谋, 李永杰, 王成润, 尹玉寿, 邱利焱, 金一.中国医药杂志, 2010, 45, 277—282)
[22]	Li F., Ba Q.J., Niu S. M., Sun J., Mater. Sci. Eng. C, 2012, 32, 2017—2025
[23]	Lee C. K., Choi J. S., Kim I. S., Byeon H. J., Kim T. H., Oh K. T., Lee E. S., Lee K. C., Youn Y. S., Acta Biomater., 2014, 10, 812—820
[24]	Yu L., Zhang H., Ding J. D., Angew. Chem. Int. Ed., 2006, 45, 2232—2235
[25]	Chen M.L., Preparation and Characterization of mPEG/CS Temperature Sensitive Hydrogel, Suzhou University, Suzhou, 2011
	(陈美玲. mPEG/CS 温敏性水凝胶的制备及性能表征, 苏州: 苏州大学, 2011)