Development of a Dual-drug-loaded Silk Fibroin Hydrogel and Study on Its Drugs Release Behaviors

doi:10.6023/A21050203

Acta Chimica Sinica ›› 2021, Vol. 79 ›› Issue (8): 1023-1029.DOI: 10.6023/A21050203 Previous Articles Next Articles

Special Issue: 分子探针、纳米生物学与生命分析化学

Article

双载药丝蛋白水凝胶的构筑及其释药性能研究

王苏杭^a, 孙灵娜^a, 曹涵^b, 钟一鸣^c, 邵正中^b^,^*()

a 深圳大学化学与环境工程学院深圳 518060
b 复旦大学聚合物分子工程国家重点实验室先进材料实验室高分子科学系上海 200433
c Babel International College, Perth, WA 6100, Australia

投稿日期:2021-05-10 发布日期:2021-06-28
通讯作者: 邵正中
基金资助:
国家自然科学基金(21704066); 国家自然科学基金(21935002); 广东省基础与应用基础研究基金项目(2021A1515010241); 深圳市高等院校稳定支持计划面上项目(20200813081943001)

Development of a Dual-drug-loaded Silk Fibroin Hydrogel and Study on Its Drugs Release Behaviors

Suhang Wang^a, Lingna Sun^a, Han Cao^b, Yiming Zhong^c, Zhengzhong Shao^b()

a College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen 518060, China
b State Key Laboratory of Molecular Engineering of Polymers, Laboratory of Advanced Materials, Department of Macromolecular Science, Fudan University, Shanghai 200433, China
c Babel International College, Perth, WA 6100, Australia

Received:2021-05-10 Published:2021-06-28
Contact: Zhengzhong Shao
Supported by:
National Natural Science Foundation of China(21704066); National Natural Science Foundation of China(21935002); Guangdong Basic and Applied Basic Research Foundation(2021A1515010241); Shenzhen Natural Science Fund (the Stable Support Plan Program)(20200813081943001)

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Abstract

Injectable hydrogels, as an effective vehicle for localized drug delivery, have attracted increasing attention in recent years. With improved tumor-specific drug accumulation and lowered risk of infection, the application of in situ-forming injectable hydrogels provides an alternative to surgical implantation. In this study, based on a unique feature of regenerated silk fibroin (RSF) that it can easily form β-sheet structures, which function as physical cross-links, under various conditions, we designed an injectable silk fibroin hydrogel which encapsulated SBA-15 for the co-delivery of a vascular disrupting agent, combretastatin A4 disodium phosphate (CA4P), and doxorubicin hydrochloride (DOX). Such a CA4P and DOX co-encapsulated hydrogel ((RSF/CA4P)-(SBA-15/DOX)), simply prepared through a designed ultrasonication procedure, showed two different types of drug release behavior. CA4P was rapidly released, and it not only targeted the abnormal vasculature of tumors, causing vascular collapse, but also inhibited tumor cell proliferation by binding to tubulin and arresting mitosis. On the other hand, the sustained release of DOX can inhibit the proliferation of tumor cells for a prolonged period of time. Because of the rapid disruption of tumor vasculature and sustained inhibition of tumor cells proliferation, the (RSF/CA4P)-(SBA-15/DOX) hydrogel showed significantly enhanced cytotoxicity against human breast carcinoma cells (MDA-MB-231). By using this co-delivery system, the required dose of DOX can be lowered, and at the same time, the superior antitumor efficacy of the drugs is maintained. Our results suggest that the application of silk fibroin hydrogels to the co-delivery of a vascular disrupting agent and a chemotherapeutic agent with different drug release behaviors is a promising strategy in tumor treatment. Moreover, after sonication, the hydrogel precursor of (RSF/CA4P)-(SBA-15/DOX), can reach target irregular-shaped tumor sites via intratumor injection, and the hydrogels then form in situ, simply induced by body heat. Such silk fibroin-based hydrogels are injectable and malleable and fluorescent in dark field, which greatly facilitates their biomedical applications.

Key words: biomacromolecule, silk fibroin, hydrogel, injectable, dual-drug release behavior

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Suhang Wang, Lingna Sun, Han Cao, Yiming Zhong, Zhengzhong Shao. Development of a Dual-drug-loaded Silk Fibroin Hydrogel and Study on Its Drugs Release Behaviors[J]. Acta Chimica Sinica, 2021, 79(8): 1023-1029.

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Figure 1. Schematic representation of the sequential drug release in dual drugs loaded hydrogel

Figure 2. SEM images of the cross section of the lyophilized RSF-(SBA-15) hydrogel

Figure 3. The rheology characterization of the RSF hydrogel and the RSF-(SBA-15) (w(SBA-15)=20%) hydrogel. (a) Storage modulus (G') versus frequency for the RSF hydrogel and the RSF-(SBA-15) hydrogel at 37 ℃. (b) Storage modulus (G') versus strain for the RSF hydrogel and the RSF-(SBA-15) hydrogel at 37 ℃

Figure 4. Illustration of the preparation of the (RSF/CA4P)- (SBA-15/DOX) hydrogel. The hydrogel was injectable, and fluorescent in dark field

Figure 5. In vitro drug release in 0.01 mol/L, pH 7.4 PBS at 37 ℃. (a) CA4P and DOX release from the (RSF/CA4P)-(SBA-15/DOX) hydrogel; (b) DOX release from the RSF-(SBA-15/DOX) and (RSF/CA4P)- (SBA-15/DOX) hydrogels with or without 5 U/mL protease XIV

Figure 6. Immunofluorescent staining of HUVEC cells. The HUVEC cells were imaged at 12 h or 24 h post-incubation with different hydrogels at 37 ℃ under an atmosphere of 5% CO2. Scale bar, 20 μm

Figure 7. In vitro cytotoxicity studies of different hydrogels were examined as a function of incubation time via CCK-8 assay. At the 4th, 9th, 14th day, the media of each well was removed and replenished with 1 mL DMEM-FBS containing 2×104 cells (at the 4th day), 5×104 cells (at the 9th day), 1×105 cells (at the 14th day)

Figure 8. Illustration representation of the detail cell experiment of hydrogels treated tumor cells

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双载药丝蛋白水凝胶的构筑及其释药性能研究

Development of a Dual-drug-loaded Silk Fibroin Hydrogel and Study on Its Drugs Release Behaviors

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