Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
Ocean College, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
Int J Pharm. 2017 Apr 30;522(1-2):210-221. doi: 10.1016/j.ijpharm.2017.02.068. Epub 2017 Mar 2.
Though Drug delivery systems have achieved accumulation at tumor sites via passive targeting and active targeting, the therapeutic effects are far from perfect. The unsatisfactory results are mainly due to limited drug release from the nanocarriers at tumor sites, while the pharmacological activities of the drug are attributed to the concentration of the free drug and the time maintained at the pharmacological targets. A pH-responsive chitosan based glycolipid-like nanocarrier (CSO-FBA-SA) was fabricated by conjugating stearyl alcohol (SA) to chitosan oligosaccharide (CSO) with the linkage of 4-formylbenzoic acid (FBA). FBA was a kind of aromatic aldehyde carbonyl compounds, which can form the benzoic-imine bond. In the presence of a Schiff's base structure, the carrier showed improved properties and could be quickly degraded in an acidic environment. In order to explore the process and mechanism of the nanocarriers in focal cells, the method for determining the intracellular concentration of released free doxorubicin was established, and the time-dependent change of the DOX-loaded micelles was revealed. The sight of drug release was also obtained with CLSM. The cytotoxicity of the CSO-FBA-SA/DOX against human breast cancer MCF-7 cells increased by 2.75-fold and 3.77-fold in comparison with the CSO-SA/DOX and DOX, respectively. Furthermore, the CSO-FBA-SA/DOX showed a 2.12-fold higher cytotoxicity against the MCF-7 cells than that treated against human ovarian cancer SKOV-3 cells with lower intracellular pH value, which indicated that the cellular inhibition positively correlated with the intracellular pH value. High tumor accumulation and fast drug release of the CSO-FBA-SA/DOX in tumor was responsible for the remarkable tumor growth inhibitory effect. Moreover, the CSO-FBA-SA/DOX could selectively respond to the acidic environment and release DOX in tumor only, which had relatively minimal cytotoxicity towards normal tissues. The results showed that this newly developed glycolipid-like nanocarrier could act as a potential vector for delivering the drug effectively with a low systemic toxicity.
尽管药物传递系统已经通过被动靶向和主动靶向在肿瘤部位实现了积累，但治疗效果远非完美。不理想的结果主要是由于纳米载体在肿瘤部位的药物释放有限，而药物的药理活性归因于游离药物的浓度和在药理靶点维持的时间。通过将硬脂醇（SA）与壳聚糖寡糖（CSO）连接，用 4-甲酰苯甲酸（FBA）偶联，制备了一种基于壳聚糖的糖脂样纳米载体（CSO-FBA-SA）。FBA 是一种芳香醛羰基化合物，可以形成苯甲酰亚胺键。在席夫碱结构存在的情况下，载体表现出更好的性能，可以在酸性环境中快速降解。为了探索纳米载体在局灶性细胞中的作用过程和机制，建立了测定释放游离阿霉素细胞内浓度的方法，揭示了载药胶束的时间依赖性变化。还通过 CLSM 获得了药物释放的图像。与 CSO-SA/DOX 和 DOX 相比，CSO-FBA-SA/DOX 对人乳腺癌 MCF-7 细胞的细胞毒性分别提高了 2.75 倍和 3.77 倍。此外，CSO-FBA-SA/DOX 对 MCF-7 细胞的细胞毒性比用低胞内 pH 值处理的人卵巢癌 SKOV-3 细胞高 2.12 倍，这表明细胞抑制与胞内 pH 值呈正相关。CSO-FBA-SA/DOX 在肿瘤中的高肿瘤积累和快速药物释放是其显著肿瘤生长抑制作用的原因。此外，CSO-FBA-SA/DOX 可以选择性地响应酸性环境，仅在肿瘤中释放 DOX，对正常组织的细胞毒性相对较小。结果表明，这种新开发的糖脂样纳米载体可以作为一种有效的药物传递载体，具有较低的全身毒性。
