摘要/Abstract
可注射水凝胶因其可以长时间在肿瘤病灶部位缓慢释放药物及避免外科手术风险等而备受关注. 本工作将载有盐酸阿霉素(DOX)的介孔硅分子筛SBA-15/DOX与混有血管阻断剂康普瑞汀磷酸二钠盐(CA4P)的再生丝蛋白(RSF)水溶液均匀混合后, 根据丝蛋白能在多种促进条件下易形成β-折叠构象并成为物理交联点/区域的特性, 通过超声法制得了具有两种不同药物释放行为的(RSF/CA4P)-(SBA-15/DOX)可注射水凝胶. 其中快速释放的CA4P, 与肿瘤血管的内皮细胞中β-微管蛋白的秋水仙碱结合位点结合, 破坏已生成的肿瘤血管, 进而阻断对肿瘤细胞的氧气输送和营养输送; 而长时间持续缓慢释放的DOX, 将抑制肿瘤细胞的生长. 具有不同药物释放动力学的良好组合, 使得(RSF/CA4P)-(SBA-15/DOX)水凝胶在较长时间内对人乳腺肿瘤细胞(MDA-MB-231)的增殖有较强的抑制作用, 同时达到了降低DOX的使用剂量但仍能保持高效的抗肿瘤细胞作用的目的. 另外, 此类水凝胶具有可塑性和可注射性, 也能在暗场下发出相应的荧光, 这为其在生物医疗方面的应用带来了极大的便利.
关键词: 生物大分子, 丝蛋白, 水凝胶, 可注射性, 双药物释放行为
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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