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.
Highlights
One of the main problems in B cell lymphoma treatment is severe adverse effects and low therapeutic efficacy resulting from systemic chemotherapy
As mentioned above and envisioned in Scheme 1, in this paper we aim to evaluate whether (a) it is possible to design an intracellular pH-responsive and targeted drug delivery system based on mesoporous silica nanoparticles (MSNs), (b) targeted drug delivery system are able to selectively adhere to CD20 antigen positive lymphoma B cells and (c) whether molecules (i.e., DOX) can be selectively delivered to CD20 antigen positive lymphoma B cells upon binding with rituximab-conjugated DMSNs (RDMSNs) via the receptor-mediated endocytosis pathway for improving the therapeutic index
Preparation and characterization of nanoparticles Scheme 1 shows the synthesis of DOX -loaded MSNs (DMSNs) and RDMSNs
Summary
One of the main problems in B cell lymphoma treatment is severe adverse effects and low therapeutic efficacy resulting from systemic chemotherapy. A chimeric monoclonal antibody that can interact with the CD20 antigen [1], combined with doxorubicin (DOX) have been extensively used for improving the prognosis of B cell lymphoma over the past few decades [2] These treatments have favorable therapeutic effects in most cases, significant adverse effects may occur due to premature drug release prior to reaching the targeted sites and nonspecific biodistribution in normal tissues [3]. Various types of targeted ligands, such as folate [24], peptides [25], glycyrrhetinic acid [26], hyaluronic acid [27], mannose [28], arginineglycine-aspartate [29], DNA aptamer [30], and lactobionic acid [31], have been successfully conjugated to drug delivery carriers, leading to an enhanced anticancer drug therapeutic index At present, these ligands primarily targeted solid tumors rather than lymphoma and were rarely used in clinical applications for cancer molecular targeting therapy due to unwanted immunogenicity. The development of intracellular pH-responsive and active targeted drug-loaded MSNs is urgently needed for minimizing the side effects and maximizing the therapeutic efficacy for lymphatic system tumors
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