Oral multistage nanomedicine for synergistic chemo/chemodynamic/near-infrared-II photothermal cancer therapy.

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-Cu2-xSe NPs) were designed using an anion exchange method and coated with calcium alginate and chitosan (AC) to form Mn-Cu2-xSe@AC capsules. The pH-responsive swelling behavior of the AC protective layer aided doxorubicin (DOX)-loaded Mn-Cu2-xSe 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-Cu2-xSe NPs was confirmed using a monolayer absorption model involving Caco-2 human epithelial cells. The released DOX/Mn-Cu2-xSe 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-Cu2-xSe 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-Cu2-xSe@AC capsules as a multistage oral drug delivery system may overcome the sequential absorption barriers that currently hinder chemotherapy, chemodynamic, and photothermal therapies.