Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China.
Engineering Research Center for Biomedical Materials, Anhui Key Laboratory of Modern Biomanufacturing, School of Life Sciences, Anhui University, 111 Jiulong Road, Hefei, Anhui Province, 230601, PR China.
Colloids Surf B Biointerfaces. 2020 Dec;196:111319. doi: 10.1016/j.colsurfb.2020.111319. Epub 2020 Aug 12.
To develop simple and effective nano-drug delivery systems remains a major challenge in cancer treatment. Herein, we synthesized an ortho ester-linked deoxycholic acid dimer (DCA-OE), which could effectively self-assemble with doxorubicin (DOX) to form stable nanoparticles (DCA-OE/DOX NPs) by a single emulsion method. DCA-based nanoparticles had a desirable size (∼200 nm), morphology (spherical shape), and high drug encapsulation (drug loading content of ∼18.0 %, drug loading efficiency of ∼77.6 %). DCA-OE could improve the stability and solubility of DOX in physiological environment, while pH-sensitive ortho ester linkage endowed the ability to release DOX quickly in cancer cells. In vitro cytotoxicity and apoptosis verified drug-loaded dimer nanoparticles had similar toxicity with free DOX. Besides, these particles could efficiently accumulate and penetrate into human liver carcinoma cell line (HepG2) multicellular spheroids, thus resulting in enhanced antitumor effect. In vivo tests further exhibited that DCA-OE/DOX NPs had lower systemic toxicity and higher tumor inhibition effect, and its tumor inhibition rate was 84.1 %, which was far more than free DOX (49.3 %). Therefore, the strategy to link functional small molecules with ortho ester has great potentials in specific delivery of anticancer drugs.
开发简单有效的纳米药物递送系统仍然是癌症治疗的主要挑战。在此，我们合成了一种邻酯键连接的脱氧胆酸二聚体（DCA-OE），它可以通过单一乳液法有效地与阿霉素（DOX）自组装形成稳定的纳米颗粒（DCA-OE/DOX NPs）。基于 DCA 的纳米颗粒具有理想的尺寸（约 200nm）、形态（球形）和高药物包封率（载药量约为 18.0%，载药效率约为 77.6%）。DCA-OE 可以提高 DOX 在生理环境中的稳定性和溶解度，而 pH 敏感的邻酯键则赋予了在癌细胞中快速释放 DOX 的能力。体外细胞毒性和细胞凋亡实验验证了载药二聚体纳米颗粒与游离 DOX 具有相似的毒性。此外，这些颗粒可以有效地聚集并渗透到人肝癌细胞系（HepG2）的多细胞球体中，从而增强抗肿瘤效果。体内实验进一步表明，DCA-OE/DOX NPs 具有较低的全身毒性和更高的肿瘤抑制作用，其肿瘤抑制率为 84.1%，远远高于游离 DOX（49.3%）。因此，将功能小分子与邻酯键连接的策略在抗癌药物的特异性递送方面具有很大的潜力。
