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

Abstract

BackgroundOne 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.MethodsIn 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.ResultsThis 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.ConclusionsThis 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.

A CXCR4-targeted nanocarrier achieves highly selective tumor uptake in diffuse large B-cell lymphoma mouse models

“…27 Regarding B-cell lymphoma therapy, the use of doxorubicin-loaded mesoporous silica nanoparticles bound to rituximab, for targeting CD20 + B cells, demonstrated a significant increase in doxorubicin tumor uptake and higher inhibition of tumor growth than free doxorubicin. 28 Moreover, additional targeted and non-targeted therapeutic nanoparticles are currently being evaluated for treatment of B-cell malignancies; however, no efficacy data are available yet because Phase I clinical assays to test their tolerability are still ongoing. 29 The strategy we have used here with the actively targeted T22-GFP-H6 nanocarrier achieves selective and enhanced biodistribution to tumor tissue with no toxicity in the non-tumor organs.…”

Mesoporous Silica Nanoparticles as Drug Delivery Vehicles in Cancer

“…They availed an epithelial growth factor receptor (EGFR)-antibody for targeting leukemic cells efficiently in vitro and in vivo [ 58 ]. Moreover, Zhou and colleagues conjugated rituximab to MSN and evaluated the drug delivery vehicle in vitro and in vivo [ 59 ]. Rituximab is a chimeric monoclonal antibody targeting the CD20 antigen on B cells and is approved amongst others for B-cell non-Hodgkin lymphoma therapy [ 60 ].…”

“…Rituximab is a chimeric monoclonal antibody targeting the CD20 antigen on B cells and is approved amongst others for B-cell non-Hodgkin lymphoma therapy [ 60 ]. In a murine xenograft lymphoma model a pronounced effect on tumor volume reduction was observed for rituximab-targeted doxorubicin-loaded MSN, while the mice constitution remained better in comparison to mice treated with free doxorubicin [ 59 ]. Furthermore, for tumor vasculature targeting anti-CD105 antibody (TRC105) has been employed by Chen et al in a murine breast cancer model.…”

“…In general, silica particles are degraded into water-soluble orthosilicic acid (Si(OH) 4 ) which is also absorbed by humans to form silica as a trace element [ 85 ]. Many in vitro studies showed no toxicity for up to 100 µg mL −1 MSN in cell culture [ 48 , 58 , 59 , 85 ]. Sometimes even higher concentrations were tested without significant toxicity [ 49 , 86 ].…”

Surface Decorated Mesoporous Silica Nanoparticles: A Promising and Emerging Tool for Cancer Targeting

“…Avidin-biodin bridging approach was undertaken and the results showed little premature release at physiological pH and enhance release in microtumor environment leading to enhanced therapeutic value and diminished off-target toxicity. 150…”