New formulated “DOX-MTX-loaded Nanoparticles” Downregulate HER2 Gene Expression and Improve the Clinical Outcome in OSCCs Model in Rat: the Effect of IV and Oral Modalities

Abstract

<b>Background:</b> Oral squamous cell carcinoma (OSCC) remains as one of the most difficult malignancies tocontrol because of its high propensity for local invasion and cervical lymph node dissemination. In this study, weevaluate the efficacy of our novel pH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles(DOX-MTX NP) in affecting HER2 expression profile in OSCC model in rat. <br/><b>Results</b>: DOX-MTX- nanoparticlecomplexes caused significant decrease in mRNA level of HER2 compared to untreated cancers (p<0.05) and thisfinding was more pronounced with the IV mode (p<0.000). Surprisingly, HER2 mRNA was not affected in DOXtreated as compared to the control group (p>0.05). On the other hand, in the DOX-MTX NP treated group, fewertumors characterized with advanced stage and decreased HER2 paralleled improved clinical outcome (P<0.05).Moreover, the effectiveness of the oral route in the group treated with nanodrug accounted for the enhancedbioavailability of nanoparticulated DOX-MTX compared to free DOX. Furthermore, there was no significantdifference in mRNA level of HER2 (p>0.05). <br/><b>Conclusions</b>: Influence of HER2 gene expression is a new featureand mechanism of action observed only in dual action DOX-MTX-NPs treated groups. Down-regulation ofHER2 mRNA as a promising marker and prognosticator of OSCC adds to the cytotoxic benefits of DOX in itsnew formulation. Both oral and IV application of this nanodrug could be used, with no preferences in term oftheir safety or toxicity. As HER2 is expressed abundantly by a wide spectrum of tumors, i DOX-MTX NPs maybe useful for a wide-spectrum of lesions. However, molecular mechanisms underlying HER2 down regulationinduced by DOX-MTX NPs remain to be addressed.