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中的主要挑战。在这里，我们合成了一种原酸酯连接的脱氧胆酸二聚体（DCA-OE），它可以与阿霉素（DOX）有效地自组装，并通过单乳液法形成稳定的纳米颗粒（DCA-OE / DOX NPs）。基于DCA的纳米粒子具有理想的尺寸（约200 nm），形态（球形）和高度的药物包封（药物负载量约为18.0％，药物负载效率约为77.6％）。DCA-OE可以改善DOX在生理环境中的稳定性和溶解性，而pH敏感的原酸酯键赋予了在癌细胞中快速释放DOX的能力。体外细胞毒性和凋亡验证载药的二聚体纳米颗粒与游离DOX具有相似的毒性。此外，这些颗粒可有效积聚并渗透到人肝癌细胞系（HepG2）多细胞球体中，从而增强抗肿瘤作用。体内试验进一步表明，DCA-OE / DOX NPs具有较低的全身毒性和较高的抑瘤作用，其抑瘤率为84.1％，远远高于游离的DOX（49.3％）。因此，将功能性小分子与原酸酯连接的策略在抗癌药物的特异性递送中具有巨大的潜力。