DOX-MTX-NPs Augment p53 mRNA Expression in OSCC Model in Rat: Effects of IV and Oral Routes


Background: Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide. Cancerdevelopment and progression require inactivation of tumor suppressor genes and activation of proto-oncogenes.The well recognized mechanism of action demonstrated for chemotherapeutic agents is induction of apoptosisvia reactivation of p53. In this context, we evaluate the efficacy of IV and oral routes of our novel PH andtemperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NP) in affecting p53 profilein an OSCC rat model.
Methods: In this study, 120 male rats were divided into 8 groups of 15 animals each. Thenew formulated DOX-MTX NP and free doxorubicin were IV and orally given to rats with 4-nitroquinoline-1-oxide induced OSCC.
Results: Results showed that both DOX and DOX-MTX-NP caused significant increasein mRNA levels of P53 compared to the untreated group (p<0.000). With both DOX and DOX-MTX NP, theIV mode was more effective than the oral (gavage) route (p<0.000). Surprisingly, in oral mode, p53 mRNA wasnot affected in DOX treated groups (p>0.05), Nonetheless, both IV and oral administration of MTX-DOX NPshowed superior activity (~3 fold) over free DOX in reactivation of p53 in OSCC (p<0.000). The effectiveness oforal route in group treated with nanodrug accounts for the enhanced bioavailability of nanoparticulated DOXMTXcompared to free DOX. Moreover, in treated groups, tumor stage was markedly related to the amountof p53 mRNA (p<0.05).
Conclusion: Both oral and IV application of our novel nanodrug possesses superioractivity over free DOX-in up-regulation of p53 in a OSCC model and this increase in p53 level associated withless aggressive tumors in our study. Although, impressive results obtained with IV form of nanodrug (-21 foldincrease in p53 mRNA level) but both forms of nanodrug are effective in OSCC, with less toxicity normal cells.