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

Abstract

Background: Oral squamous cell carcinoma (OSCC) remains as one of the most difficult malignancies to control because of its high propensity for local invasion and cervical lymph node dissemination. In this study, we evaluate 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. Results: DOX-MTX-nanoparticle complexes caused significant decrease in mRNA level of HER2 compared to untreated cancers (p<0.05) and this finding was more pronounced with the IV mode (p<0.000). Surprisingly, HER2 mRNA was not affected in DOX treated as compared to the control group (p>0.05). On the other hand, in the DOX-MTX NP treated group, fewer tumors 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 enhanced bioavailability of nanoparticulated DOX-MTX compared to free DOX. Furthermore, there was no significant difference in mRNA level of HER2 (p>0.05). Conclusions: Influence of HER2 gene expression is a new feature and mechanism of action observed only in dual action DOX-MTX-NPs treated groups. Down-regulation of HER2 mRNA as a promising marker and prognosticator of OSCC adds to the cytotoxic benefits of DOX in its new formulation. Both oral and IV application of this nanodrug could be used, with no preferences in term of their safety or toxicity. As HER2 is expressed abundantly by a wide spectrum of tumors, i DOX-MTX NPs may be useful for a wide-spectrum of lesions. However, molecular mechanisms underlying HER2 down regulation induced by DOX-MTX NPs remain to be addressed.

Nanomedicine, an emerging therapeutic strategy for oral cancer therapy

“…Apoptosis and DNA damage was significantly increased in the dual-drug-loaded liposome group compared to other controls. Abbasi et al [53][54][55] examined stimuli-responsive cationic mesoporous silica NPs loaded with MTX and Dox on a 4-NQO-induced oral cavity SCC rat model. Both free and nanoforms of Dox combined with MTX were orally or IV administrated for 14 weeks.…”

Anti Proliferative Properties of Melissa officinalis in Different Human Cancer Cells

“…These 4 cancers account for almost half of the total cancer deaths among men and women, with more than one-quarter of all cancer deaths due to lung cancer. An urgent need in cancer control today is to develop effective and affordable approaches to the early detection, diagnosis, and treatment of cancer (Abbasi et al, 2014b;Siegel et al, 2014).…”

Development and in�vitro evaluation of mucoadhesive patches of methotrexate for targeted delivery in oral cancer

“…The HSC-3 cell line is highly invasive; therefore, the present study aimed to detect the mechanism of MTX-induced apoptosis in HSC3 cells. MTX is active in oral cancer cells, but exhibits marked limitations regarding cell uptake and site specificity as it is associated with certain highly toxic effects (17). This was also evaluated via an apoptosis assay in HSC 3 cells; M-LP-F7 increased the percentage of apoptotic cells 3-fold, compared with MTX alone.…”

“…Additionally, HPMC and PVA exhibited an extended release of almost 40% of the drug in 12 h. Abbasi et al (17) formulated a doxorubicin-methotrexate (MTX)-loaded nanoparticle to attenuate oral cancer growth, and evaluated them in an oral squamous cell carcinoma (OSCC) rat model. Additionally, this study group identified that the downregulation of matrix metalloproteinase 2 and receptor tyrosine-protein kinase ErbB-2 gene expression in an OSCC rat model were responsible for the clinical outcomes observed (17,18). MTX is a commonly used anticancer agent for various types of cancer, including colon, breast, skin and head and neck cancer (19)(20)(21).…”