Transferrin-targeting pH-responsive and biodegradable mesoporous silica nanohybrid for nitric oxide-sensitized chemotherapy of cancer

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.