庚酰化乙二醇壳聚糖温敏性水凝胶的制备及其药物缓释

韩晓杰; 李征征

doi:10.13801/j.cnki.fhclxb.20230825.004

庚酰化乙二醇壳聚糖温敏性水凝胶的制备及其药物缓释

doi: 10.13801/j.cnki.fhclxb.20230825.004

韩晓杰^{1, 2},
李征征^{1, 3, ,}

1.
天津科技大学　化工与材料学院，天津 300457
2.
沂水县第四中学，临沂 276405
3.
复旦大学　聚合物分子工程国家重点实验室，上海 200433

基金项目: 2018年度天津市教委科研计划项目(2018KJ110)；2021年天津市研究生科研创新项目(2021YJSS048)

详细信息

通讯作者:
李征征，博士，副研究员，硕士生导师，研究方向为智能高分子水凝胶及其生物医用研究　E-mail: Li.z.z@tust.edu.cn

中图分类号: O63；TB332
计量
- 文章访问数: 370
- HTML全文浏览量: 152
- PDF下载量: 14
- 被引次数: 0
出版历程
- 收稿日期: 2023-07-07
- 修回日期: 2023-08-01
- 录用日期: 2023-08-12
- 网络出版日期: 2023-08-28
- 刊出日期: 2024-05-15

Preparation of heptanoylated glycol chitosan thermo-sensitive hydrogel for sustained drug release

HAN Xiaojie^{1, 2},
LI Zhengzheng^{1, 3
, ,}

1.
School of Chemical Engineering and Materials, Tianjin University of Science and Technology, Tianjin 300457, China
2.
Yishui County No. 4 Middle School, Linyi 276405, China
3.
State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai 200433, China

Funds: Tianjin Education Commission Scientific Research Program Project (2018KJ110); 2021 Tianjin Graduate Research Innovation Project (2021YJSS048)

摘要

摘要: 为了制备一种物理交联的温敏性水凝胶，本文选择水溶性乙二醇壳聚糖(GC)作为基体，通过庚酸酐与GC分子链上的氨基进行酰化反应实现改性，合成了具有不同庚酰度(DS)的庚酰化乙二醇壳聚糖(HAGC)。庚酸酐与GC分子链上氨基的进料摩尔比在0.2~0.25之间，DS介于26.4%~31.5%。通过在GC骨架上引入疏水性庚酰基团，提高GC在有机溶剂中的溶解度和体外生物降解性，而且还引入了温敏性溶胶-凝胶转变性质。HAGC通过分子间相互作用 (氢键和亲疏水相互作用) 发生物理交联，响应环境温度变化而发生溶胶-凝胶相变，通过改变HAGC的DS和溶液浓度，可有效调节HAGC水凝胶的溶胶-凝胶转变温度处于25~37℃之间。HAGC水凝胶具有三维多孔结构，随着DS增加，HAGC水凝胶的交联密度增大、溶胀比降低、药物释放速率减慢。HAGC水凝胶对吉西他滨具有缓释作用，药物释放时间可达5天，药物释放率达到70%~91%。HAGC水凝胶以其优良的温敏性能，在药物注射载体领域具有重要的应用价值。
- 乙二醇壳聚糖 /
- 庚酰化 /
- 温敏性水凝胶 /
- 溶胶-凝胶转变 /
- 药物缓释
Abstract: In order to prepare a physically cross-linked thermo-sensitive hydrogel, in this paper, water-soluble glycol chitosan (GC) was selected as the matrix, the heptanoylated glycol chitosan (HAGC) with different degrees of heptanoylation (DS) were synthesized by acylation modification through amide coupling reaction between heptanoic anhydride and amino groups on the molecular chain of GC. The results show that the feed molar ratio of heptanoic anhydride to the amino group on GC is between 0.2 and 0.25, and DS is modulated from 26.4% to 31.5%. By the introduction of hydrophobic acetyl groups on the backbone of GC, it was not only found that such derivatization would improve the solubility in organic solvents and in vitro biodegradability of GC, but also import new attractive properties such as thermo-sensitive sol-gel transition properties. HAGC was physically cross-linked through intermolecular interactions, including hydrogen bonding and hydrophilic and hydrophobic interactions. Thus, HAGC could undergo sol-gel phase transition in response to ambient temperature changes. By changing the DS and solution concentration of HAGC, the sol-gel transition temperature of HAGC hydrogel was effectively adjusted between room temperature and human body temperature (25-37℃) . The HAGC hydrogel had the three-dimensional porous structure. As the DS increase, the crosslink density of the HAGC hydrogel increased, the swelling ratio decreased, and the drug release rate slowed down. The HAGC hydrogel had a slow-release effect on the drug gemcitabine, and the drug release time could reach 5 days, and the drug release rate was up to 70%-91%. Therefore, HAGC hydrogel has important application value in biomedical fields such as drug injection and sustained-release carrier due to its excellent thermo-sensitive properties.
- glycol chitosan /
- heptanoylation /
- thermo-sensitive hydrogel /
- sol-gel transition /
- drug release

HTML全文

图 1 庚酰化乙二醇壳聚糖 (HAGC)温敏性水凝胶的合成路线示意图

Figure 1. Synthetic procedure of heptanoylated glycol chitosan (HAGC) thermo-sensitive hydrogel

下载: 全尺寸图片幻灯片

图 2 乙二醇壳聚糖(GC)、HAGC1、HAGC2和HAGC3的FTIR图谱

Figure 2. FTIR spectra of glycol chitosan (GC), HAGC1, HAGC2 and HAGC3

下载: 全尺寸图片幻灯片

图 3 GC、HAGC1、HAGC2和HAGC3的¹H NMR图谱

Figure 3. ¹H NMR spectra of GC, HAGC1, HAGC2 and HAGC3

下载: 全尺寸图片幻灯片

图 4 HAGC水凝胶的SEM图像：((a₁), (a₂)) HAGC1 (3wt%)；((b₁), (b₂)) HAGC2 (3wt%)；((c₁), (c₂)) HAGC3 (3wt%)

Figure 4. SEM images of HAGC: ((a₁), (a₂)) HAGC1 (3wt%); ((b₁), (b₂)) HAGC2 (3wt%); ((c₁), (c₂)) HAGC3 (3wt%)

下载: 全尺寸图片幻灯片

图 5 试管反转法测定的HAGC的溶胶-凝胶转变相图

Figure 5. Sol-gel transition phase diagram of HAGC by the tube inverting method

下载: 全尺寸图片幻灯片

图 6 (a) HAGC的溶胶-凝胶转变示意图；(b) HAGC的可逆相变；(c) HAGC的可注射性示意图；(d) 3wt%HAGC3在37℃时呈凝胶状态

RT—Room temperature

Figure 6. (a) Schematic diagram of sol-gel transition of HAGC; (b) Reversible phase transition of HAGC; (c) Injectability diagram of HAGC; (d) Gel form of 3wt%HAGC3 at 37℃

下载: 全尺寸图片幻灯片

图 7 HAGCs水凝胶的温度依赖性流变行为：(a) HAGC2 (3wt%)； (b) HAGC3 (3wt%)； (c) HAGC2 (4wt%)；(d) HAGC3 (4wt%)

T—Temperature; G'—Storage modulus; G"—Loss modulus

Figure 7. Temperature dependent rheological behavior of HAGC hydrogels: (a) HAGC2 (3wt%); (b) HAGC3 (3wt%); (c) HAGC2 (4wt%); (d) HAGC3 (4wt%)

下载: 全尺寸图片幻灯片

图 8 HAGC1、HAGC2和HAGC3水凝胶的溶胀速率

Figure 8. Swelling rate of HAGC1, HAGC2 and HAGC3 hydrogels

下载: 全尺寸图片幻灯片

图 9 HAGC水凝胶在溶菌酶溶液中的体外降解

Figure 9. Degradation of HAGC hydrogels in lysozyme solution

下载: 全尺寸图片幻灯片

图 10 载有吉西他滨的HAGC水凝胶的体外药物释放曲线

Figure 10. In vitro drug release profiles of gemcitabine loaded HAGC hydrogels

下载: 全尺寸图片幻灯片

表 1 HAGC的合成配比

Table 1. Synthetic ratio of HAGC

Sample	Molar ratio^a	DS^b/%	Yield/%
HAGC1	0.20∶1	26.4	86.3
HAGC2	0.22∶1	29.6	89.9
HAGC3	0.24∶1	31.3	87.0
Notes: ^a—Feed molar ratio of heptanoic anhydride to the amino group of glycol chitosan; ^b—Degree of heptanoylation determined by the peak integration of ¹H NMR; DS—Degree of heptanoylation.

下载: 导出CSV

表 2 HAGC水凝胶对吉西他滨的释放机制

Table 2. Release characteristics of encapsulated gemcitabine from HAGC hydrogels

Sample	k	n	Release characteristics
HAGC1	0.44	0.20	pseudo-Fickian
HAGC2	0.46	0.23	pseudo-Fickian
HAGC3	0.51	0.36	pseudo-Fickian
Notes: k—Rate constant; n—Release index.

下载: 导出CSV

参考文献(22)

[1]	KADRI R, BACHAROUCH J, ELKHOURY K, et al. Role of active nanoliposomes in the surface and bulk mechanical properties of hybrid hydrogels[J]. Materials Today Bio,2020,6:100046. doi: 10.1016/j.mtbio.2020.100046
[2]	WANG Y, WU Y, LONG L Y, et al. Inflammation-responsive drug-loaded hydrogels with sequential hemostasis, antibacterial, and anti-inflammatory behavior for chronically infected diabetic wound treatment[J]. ACS Applied Materials & Interfaces,2021,13(28):33584-33599.
[3]	MISHRA B, UPADHYAY M, ADENA S K R, et al. Hydrogels: An introduction to a controlled drug delivery device, synthesis and application in drug delivery and tissue engineering[J]. Biomicrofluidics,2017,4(1):1037-1049.
[4]	HUANG Q T, ZOU Y J, ARNO M C, et al. Hydrogel scaffolds for differentiation of adipose-derived stem cells[J]. Chemical Society Reviews,2017,46(20):6255-6275. doi: 10.1039/C6CS00052E
[5]	HSU S C, HSU S H, CHANG S W. Effect of pH on molecular structures and network of glycol chitosan[J]. ACS Biomaterials Science & Engineering,2020,6(1):298-307.
[6]	WU M Y, LONG Z, XIAO H N, et al. Recent research progress on preparation and application of N, N, N-trimethyl chitosan[J]. Carbohydrate Research,2016,434:27-32. doi: 10.1016/j.carres.2016.08.002
[7]	楚立凯, 岳凌, 杨占山. 壳聚糖温敏性水凝胶蛋白载体的制备及其性能研究[J]. 复旦学报(自然科学版), 2015, 54(5):609-615. CHU Likai, YUE Ling, YANG Zhanshan. Preparation and properties of chitosan thermosensitive hydrogels for protein drug delivery[J]. Journal of Fudan University (Natural Science),2015,54(5):609-615(in Chinese).
[8]	HADDOW P, MCAULEY W J, KIRTON S, et al. Poly(N-isopropyl acrylamide)-poly(ethylene glycol)-poly (N-isopropyl acrylamide) as a thermoreversible gelator for topical administration[J]. Materials Advances,2020,1(3):371-386. doi: 10.1039/D0MA00080A
[9]	FREDRICK R, PODDER A, VISWANATHAN A, et al. Synthesis and characterization of polysaccharide hydrogel based on hydrophobic interactions[J]. Journal of Applied Polymer Science,2019,136(25):47665. doi: 10.1002/app.47665
[10]	WANG Q, HE Y, SHEN M, et al. Precision embolism: Biocompatible temperature-sensitive hydrogels as novel embolic materials for both mainstream and peripheral vessels[J]. Advanced Functional Materials, 2021, 31(20): 2011170.
[11]	FAN B E, CUI N F, XU Z W, et al. Thermoresponsive and self-healing hydrogel based on chitosan derivatives and polyoxometalate as an antibacterial coating[J]. Biomacromolecules,2022,23(3):972-982. doi: 10.1021/acs.biomac.1c01368
[12]	ZHOU L, DAI C, FAN L, et al. Injectable self-healing natural biopolymer-based hydrogel adhesive with thermoresponsive reversible adhesion for minimally invasive surgery[J]. Advanced Functional Materials,2021,31(14):2007457. doi: 10.1002/adfm.202007457
[13]	VASHAHI F, MARTINEZ M R, DASHTIMOGHADAM E, et al. Injectable bottlebrush hydrogels with tissue-mimetic mechanical properties[J]. Science Advances,2022,8(3):2469. doi: 10.1126/sciadv.abm2469
[14]	GONSALVES A, TAMBE P, LE D, et al. Synthesis and characterization of a novel pH-responsive drug-releasing nanocomposite hydrogel for skin cancer therapy and wound healing[J]. Journal of Materials Chemistry B,2021,9(46):9533-9546. doi: 10.1039/D1TB01934A
[15]	RUEL-GARIÉPY E, CHENITE A, CHAPUT C, et al. Characterization of thermosensitive chitosan gels for the sustained delivery of drugs[J]. International Journal of Pharmaceutics,2000,203(1-2):89-98. doi: 10.1016/S0378-5173(00)00428-2
[16]	李征征, 徐子扬, 高留意, 等. 温敏性乙二醇壳聚糖水凝胶的制备及药物缓释性能[J]. 高等学校化学学报, 2016, 37(12):2299-2305. doi: 10.7503/cjcu20160513 LI Zhengzheng, XU Ziyang, GAO Liuyi, et al. Preparation and characterization of thermo-sensitive N-acetyl glycol chitosan hydrogel for sustained drug release[J]. Chemical Journal of Chinese Universities,2016,37(12):2299-2305(in Chinese). doi: 10.7503/cjcu20160513
[17]	BEHERA S, MAHANWAR P A. Superabsorbent polymers in agriculture and other applications: A review[J]. Polymer-Plastics Technology & Materials,2020,59(4):341-356.
[18]	WANG S, CHI J H, JIANG Z W, et al. A self-healing and injectable hydrogel based on water-soluble chitosan and hyaluronic acid for vitreous substitute[J]. Carbohydrate Polymers,2021,256:117519. doi: 10.1016/j.carbpol.2020.117519
[19]	石士慧, 潘卫东. 盐酸吉西他滨壳聚糖纳米粒的制备及其体外释药特性研究[J]. 中国新药杂志, 2011, 20(23):2372-2376. SHI Shihui, PAN Weidong. Preparation and in vitro release characteristics of gemcitabine hydrochloride chitosan nanoparticles[J]. Chinese Journal of New Drugs,2011,20(23):2372-2376(in Chinese).
[20]	许超. 吉西他滨水凝胶的设计合成及其在胰腺癌的抗癌效果研究[D]. 天津: 天津医科大学, 2016. XU Chao. Design and synthesis of gemcitabine hydrogel and its anticancer effect in pancreatic cancer[D]. Tianjin: Tianjin: Tianjin Medical University, 2016 (in Chinese).
[21]	支东彦. 高分子凝胶的制备、药物释放及其分子热力学研究[D]. 上海: 华东理工大学, 2013. ZHI Dongyan. Synthesis, drug release and molecular thermodynamic model of polymer hydrogels[D]. Shanghai: East China University of Science and Technology, 2013 (in Chinese).
[22]	FATHI M, ALAMI-MILANI M, GERANMAYEH M H, et al. Dual thermo-and pH-sensitive injectable hydrogels of chitosan/poly(N-isopropylacrylamide-co-itaconic acid) for doxorubicin delivery in breast cancer[J]. International Journal of Biological Macromolecules,2019,128:957-964. doi: 10.1016/j.ijbiomac.2019.01.122