聚合物复合物层层组装膜的高效负载及大分子和小分子药物的差别性释放

doi:10.7503/cjcu20180408

高等学校化学学报 ›› 2019, Vol. 40 ›› Issue (3): 592.doi: 10.7503/cjcu20180408

聚合物复合物层层组装膜的高效负载及大分子和小分子药物的差别性释放

陈栋栋², 宋文植³, 李慧³, 何丹¹, 孙俊奇², 尹万忠¹()

1. 吉林大学第一临床医院, 长春 130021
2. 吉林大学超分子结构与材料国家重点实验室, 化学学院, 长春 130012
3. 吉林大学中日联谊医院, 长春 130031

收稿日期:2019-06-04 出版日期:2019-03-10 发布日期:2019-01-24
作者简介:联系人简介: 尹万忠, 男, 博士, 副教授, 主要从事纳米材料和高分子材料技术在头颈外科的应用研究. E-mail: yinwz@jlu.edu.cn
基金资助:
国家自然科学基金(批准号: 3A413AK53428, 81372900)和吉林省科技厅项目(批准号: 20180414014GH)资助.

Layer-by-layer Assembled Polymeric Complexes Films for High Loading and Differential Release of Macromolecular and Small Molecular Drugs^†

CHEN Dongdong², SONG Wenzhi³, LI Hui³, HE Dan¹, SUN Junqi², YIN Wanzhong^1,^*()

1. The First Clinical Hospital, Jilin University, Changchun 130021, China
2. State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry,Jilin University, Changchun 130012, China
3. China-Japan Union Hospital, Jilin University, Changchun 130031, China

Received:2019-06-04 Online:2019-03-10 Published:2019-01-24
Contact: YIN Wanzhong E-mail:yinwz@jlu.edu.cn
Supported by:
† Supported by the National Natural Science Foundation of China(Nos.3A413AK53428, 81372900) and the Project of Science and Technology Department of Jilin Province, China(No.20180414014GH).

摘要/Abstract

摘要：

基于聚合物复合物和层层组装技术实现了大分子药物硫酸软骨素和小分子药物头孢曲松钠在聚合物膜中的高效负载以及差别性释放. 壳聚糖(CHI)和大分子药物硫酸软骨素(CSS)通过静电相互作用力复合, 制备了壳聚糖-硫酸软骨素复合物(CHI-CSS). 以CHI-CSS复合物和透明质酸(HA)为构筑基元, 通过层层组装构筑负载有硫酸软骨素的聚合物复合物膜. 利用后扩散的负载方法将小分子药物头孢曲松钠(CTX)负载到聚合物膜中, 从而实现大分子和小分子2种药物在聚合物膜中的负载. 聚合物膜中负载的CTX和CSS在生理条件下具有快慢不同的差别性释放动力学特性, CTX在6 h内快速释放, 而CSS长效缓释长达14 d. 快速释放的抗生素CTX能够有效抑制细菌感染, 而酶降解作用下缓慢释放的CSS可促进伤口愈合, 在包括头颈外科在内的外科术后感染防治领域有良好应用前景.

关键词: 层层组装, 聚合物复合物, 聚合物膜, 药物传递, 差别性释放

Abstract:

The layer-by-Layer(LbL) assembled polymeric complexes films capable of differential release of macromolecular and small molecular drugs were fabricated by utilizing chitosan(CHI) hydrochloride-chondroitin sulfate sodium(CSS) complexes(denoted as CHI-CSS complexes) as building blocks and post-diffusion of ceftriaxone sodium(CTX). The CHI-CSS complexes were prepared by pre-assembled macromolecular drugs CSS with CHI, and then were LbL assembled with hyaluronic acid(HA) to produce CHI-CSS/HA polymeric films. The small molecular drugs CTX were loaded into the CHI-CSS/HA polymeric films through a postdiffusion process. The as-prepared CHI-CSS/HA polymeric films possess high loading capacity because of the high encapsulation amount of CSS in CHI-CSS complexes and plenty of electrostatic binding sites for CTX provided by film component CHI. CTX can be quickly released from the polymeric films because of the brea-kage of its electrostatic interaction with film component CHI. Meanwhile, the CSS can be released in sustained manner by enzymatic degradation of the films. The synergetic therapeutic effects can be achieved by fast release of antibiotic drug CTX to effectively eliminate bacteria and by sustained release of CSS to promote wound healing. The present work provides a facile way to fabricate polymeric films for high loading and diffe-rential release of multiple therapeutic agents.

Key words: Layer-by-Layer(LbL) assembly, Polymeric complex, Polymeric film, Drug delivery, Differential release

中图分类号:

O631

TrendMD:

陈栋栋, 宋文植, 李慧, 何丹, 孙俊奇, 尹万忠. 聚合物复合物层层组装膜的高效负载及大分子和小分子药物的差别性释放. 高等学校化学学报, 2019, 40(3): 592.

CHEN Dongdong, SONG Wenzhi, LI Hui, HE Dan, SUN Junqi, YIN Wanzhong. Layer-by-layer Assembled Polymeric Complexes Films for High Loading and Differential Release of Macromolecular and Small Molecular Drugs^†. Chem. J. Chinese Universities, 2019, 40(3): 592.

图/表 7

Scheme 1 Schematic illustration of the formation of CHI-CSS polyelectrolyte complexes(Ⅰ), and the layer-by-layer assembly process for the fabrication of CHI-CSS/HA polymeric films(Ⅱ)

Fig.1 Hydrodynamic diameter distribution curve of the aqueous CHI-CSS complex dispersion at pH=6.0Inset is the photograph of the aqueous CHI-CSS complex dispersion.

Fig.2 Typical QCM frequency decreases for the alternate deposition of CHI-CSS complexes(■) and HA(●)(A), thickness of CHI-CSS/HA films as a function of the number of deposition cycles(B) and top view(C) and cross-sectional(D) SEM images of (CHI-CSS/HA)×13 films

Fig.3 Time-depended release profile of CTX(A) and CSS(B) from (CHI-CSS/HA)×13 films in PBS(0.01 mol/L) containing lysozyme(2 mg/mL) at pH=7.4 and 37 ℃

Fig.4 Inhibition of E. coli(A, C) and B. subtilis(B, D) growth by release of CTX from (CHI-CSS/HA)×13 films loaded with CTXAgar plates of E. coli.(A) and B. subtilis(B) treated with the control sample(bare silicon substrate) and (CHI-CSS/HA)×13 films with and without CTX. The growth curves of E. coli(C) and B. coli(D) incubated for 24 h with the control sample(bare silicon substrate) and (CHI-CSS/HA)×13 films with CTX.

Fig.5 Bioactivity of released CSS from (CHI-CSS/HA)×13 films on wound healing in vitroThe mouse fibroblast L929 cells with wound gap incubated for 48 h with growth medium containing released CSS(A), free CSS(B) and blank PBS(C). (D) Statistical analysis of wound healing for L929 cells incubated with blank PBS(negative control), free CSS(positive control) and released CSS.

Fig.6 SEM images of surgical sutures(A, C) and bandages(B, D) before(A, B) and after(C, D) depositing with (CHI-CSS/HA)×13 films

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聚合物复合物层层组装膜的高效负载及大分子和小分子药物的差别性释放

Layer-by-layer Assembled Polymeric Complexes Films for High Loading and Differential Release of Macromolecular and Small Molecular Drugs^†

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聚合物复合物层层组装膜的高效负载及大分子和小分子药物的差别性释放

Layer-by-layer Assembled Polymeric Complexes Films for High Loading and Differential Release of Macromolecular and Small Molecular Drugs†

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Layer-by-layer Assembled Polymeric Complexes Films for High Loading and Differential Release of Macromolecular and Small Molecular Drugs^†