Yin Hongxiu, Gao Ying, Zhou Xue, Chen Xiangjun, Hu Zhichao, Zhang Lingyu, Li Lu, Wang Chungang
Department of Chemistry, Northeast Normal University, Changchun 130024, PR China.
Department of Stomatology, No. 964 Hospital, Changchun, Jilin 130021, PR China.
J Colloid Interface Sci. 2025 Apr 15;684(Pt 1):244-253. doi: 10.1016/j.jcis.2025.01.026. Epub 2025 Jan 6.
The oral administration of drugs for cancer therapy can maintain optimal blood concentrations, is biologically safe and simple, and is preferred by many patients. However, the complex lumen environment, mucus layer, and intestinal epithelial cells are biological barriers that hinder the absorption of orally administered drugs. In this study, sea urchin-like manganese-doped copper selenide nanoparticles (Mn-CuSe NPs) were designed using an anion exchange method and coated with calcium alginate and chitosan (AC) to form Mn-CuSe@AC capsules. The pH-responsive swelling behavior of the AC protective layer aided doxorubicin (DOX)-loaded Mn-CuSe NPs in overcoming multiple biological barriers, maintained their stability in gastric acid, and facilitated the release of the NPs in the small intestine. The intestinal epithelial cell permeability of DOX/Mn-CuSe NPs was confirmed using a monolayer absorption model involving Caco-2 human epithelial cells. The released DOX/Mn-CuSe NPs smoothly passed through the mucus layer, and were absorbed by intestinal epithelial cells. In mice, the NPs circulated in the blood and passively targeted the tumors through blood circulation by enhancing the permeability and retention effect to achieve significant tumor suppression and reduce damage to normal tissues. In addition, the unique sea urchin-like morphology of Mn-CuSe NPs enhanced the absorption in the near-infrared-II (NIR-II) window for photothermal therapy, realized the near-infrared-stimulated response release of DOX for increased chemotherapy, and promoted the Fenton-like effect because of the doping of manganese ions for chemodynamic therapy. These effects could permit the development of various synergistic cancer treatments. The use of DOX/Mn-CuSe@AC capsules as a multistage oral drug delivery system may overcome the sequential absorption barriers that currently hinder chemotherapy, chemodynamic, and photothermal therapies.
口服抗癌药物能够维持最佳血药浓度，具有生物安全性且使用简便，因而受到众多患者的青睐。然而，复杂的管腔环境、黏液层和肠上皮细胞构成了阻碍口服药物吸收的生物屏障。在本研究中，采用阴离子交换法设计了海胆状掺锰硒化铜纳米颗粒（Mn-CuSe NPs），并用海藻酸钙和壳聚糖（AC）进行包覆，形成Mn-CuSe@AC胶囊。AC保护层的pH响应溶胀行为有助于负载阿霉素（DOX）的Mn-CuSe NPs克服多种生物屏障，在胃酸中保持其稳定性，并促进纳米颗粒在小肠中的释放。使用包含Caco-2人上皮细胞的单层吸收模型证实了DOX/Mn-CuSe NPs的肠上皮细胞通透性。释放出的DOX/Mn-CuSe NPs顺利穿过黏液层，并被肠上皮细胞吸收。在小鼠体内，纳米颗粒在血液中循环，并通过增强渗透和滞留效应经血液循环被动靶向肿瘤，从而实现显著的肿瘤抑制并减少对正常组织的损伤。此外，Mn-CuSe NPs独特的海胆状形态增强了在近红外-II（NIR-II）窗口的光热治疗吸收，实现了近红外刺激响应释放DOX以增强化疗效果，并由于锰离子的掺杂促进了类芬顿效应以进行化学动力学治疗。这些效应有助于开发各种协同抗癌治疗方法。将DOX/Mn-CuSe@AC胶囊用作多阶段口服给药系统可能会克服目前阻碍化疗、化学动力学和光热治疗的连续吸收障碍。
