Intracellular pH-responsive and rituximab-conjugated mesoporous silica nanoparticles for targeted drug delivery to lymphoma B cells

摘要

Background One of the main problems in B cell lymphoma treatment is severe adverse effects and low therapeutic efficacy resulting from systemic chemotherapy. A pH-sensitive controlled drug release system based on mesoporous silica nanoparticles was constructed for targeted drug delivery to tumor cells to reduce systemic toxicity and improve the therapeutic efficacy. Methods In this study, the doxorubicin (DOX) was filled into the mesopores of the functional MSNs (DMSNs). Furthermore, rituximab was introduced as the targeted motif of functional DMSNs using an avidin-biotin bridging method to evaluate the targetability to tumor cells. Then, the cell viability and apoptosis efficiency after treatment with rituximab-conjugated DMSNs (RDMSNs) were estimated by using CCK-8 assay and flow cytometry, respectively. Additionally, the research in vivo was performed to evaluate the enhanced antitumor efficacy and the minimal toxic side effects of RDMSNs. Also, TUNEL staining assay was employed to explore the mechanism of antitumor effects of RDMSNs. Results This targeted drug delivery system exhibited low premature drug release at a physiological pH and efficient pH-responsive intracellular release under weakly acidic conditions. The in vitro tests confirmed that targeted RDMSNs could selectively adhere to the surface of lymphoma B cells via specific binding with the CD20 antigen and be internalized into CD20 positive Raji cells but few CD20 negative Jurkat cells, which leads to increased cytotoxicity and apoptosis of the DOX in Raji cells due to the release of the entrapped DOX with high efficiency in the slightly acidic intracellular microenvironment. Furthermore, the in vivo investigations confirmed that RDMSNs could efficiently deliver DOX to lymphoma B cells by pH stimuli, thus inducing cell apoptosis and inhibiting tumor growth, while with minimal toxic side effects. Conclusions This targeted and pH-sensitive controlled drug delivery system has the potential for promising application to enhance the therapeutic index and reduce the side effects of B cell lymphoma therapy.