Weakly acidic pH, low oxygen and high glutathione levels are the main characteristics of tumor cells. Taking advantage of the unique acidic microenvironment of tumor cells, acid-responsive mesoporous organosilica nanoparticles (AMON) were designed for nitric oxide (NO)-sensitized chemotherapy of tumors. AMON served as a nanocarrier co-loaded with a nitric oxide donor (NOD) and chemotherapeutic drug doxorubicin (DOX). Transferrin (Tf) was modified on the surface as a targeting ligand to form NOD&DOX@AMON. In vitro experiments showed that AMON could be completely degraded under acidic conditions (pH 5.0) after 48 h. NOD&DOX@AMON entered cells via transferrin receptor-mediated internalization and degraded in the acidic microenvironment to release its payloads. NOD released NO in presence of one-electron reducing substances like Glutathione (GSH) and ascorbic acid, inhibiting P-glycoprotein(P-gp) function and thereby increasing the intracellular concentration of DOX. In vivo distribution studies revealed that the nanohybrids accumulated maximally in tumor tissue 12 h after intravenous injection and exhibited significant inhibitory effects on HepG2 xenograft tumors. Western blot experiments demonstrated that NOD&DOX@AMON could inhibit the expression of drug resistance-associated proteins and was expected to be employed as a therapeutic approach for drug-resistant ttumors.
Keywords: Biodegradable mesoporous organosilica; Drug-resistant inhibition; Nitric oxide sensitization; PH-responsive.
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