PH-responsive sustained delivery of doxorubicin using aminated and PEGylated mesoporous silica nanoparticles leads to enhanced antitumor efficacy in pre-clinical orthotopic breast cancer model

Abstract

Doxorubicin (Dox) is one of the chemotherapeutic drugs used in the treatment of breast cancers. However, doxorubicin-mediated toxicity limits its use in clinics. In this study, mesoporous silica nanoparticles (MSN) were prepared by the sol-gel method. Further, it was aminated and then Dox was loaded into its pores. Subsequently, Dox-loaded MSN was coated with polyethylene glycol (PEG) and further attached with targeting moieties, such as folic acid (FA) or hyaluronic acid (HA). TEM images reveal that the average diameter of MSN is 90 nm, which increases to 107 nm after coating PEG over the surface of MSN. At pH 5.5 the drug gets slowly released over a time of 120 h. In vitro cytotoxicity demonstrates that free Dox has higher cytotoxicity than Dox-loaded nanoparticles. However, a non-invasive molecular imaging-guided preclinical study, using the 4T1 orthotopic breast cancer model demonstrates that Dox-loaded MSN formulations inhibited tumor growth to a significant level. In fact, free Dox-treated mice died after only three doses, due to its severe toxicity, which is also evident from the low spleen index, biochemical, and histopathology analysis. Further, it is observed from the survival curve that, MSN–NH2–Dox-PEG-FA and MSN–NH2–Dox-PEG-HA extend the survival of the mice up to 35 days with reduced side effects. Therefore, targeted PEGylated MSN can be used as a carrier to deliver Dox to cancer patients and possibly reduce the side effects.