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

  • Abbasi, Mehran Mesgari (Drug Applied Research Center) ;
  • Khiavi, Monir Moradzadeh (Department of Oral Pathology, Faculty of Dentistry, Tehran University of Medical Sciences, International Campus) ;
  • Monfaredan, Amir (Department of Hematology, Faculty of Medicine, Tabriz Branch, Islamic Azad University) ;
  • Hamishehkar, Hamed (Drug Applied Research Center) ;
  • Seidi, Khaled (Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences) ;
  • Jahanban-Esfahlan, Rana (Student Research Committee)
  • Published : 2014.10.23

Abstract

Background: Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide. Cancer development 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 apoptosis via reactivation of p53. In this context, we evaluate the efficacy of IV and oral routes of our novel PH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NP) in affecting p53 profile in an OSCC rat model. Methods: In this study, 120 male rats were divided into 8 groups of 15 animals each. The new 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 increase in mRNA levels of P53 compared to the untreated group (p<0.000). With both DOX and DOX-MTX NP, the IV mode was more effective than the oral (gavage) route (p<0.000). Surprisingly, in oral mode, p53 mRNA was not affected in DOX treated groups (p>0.05), Nonetheless, both IV and oral administration of MTX-DOX NP showed superior activity (~3 fold) over free DOX in reactivation of p53 in OSCC (p<0.000). The effectiveness of oral route in group treated with nanodrug accounts for the enhanced bioavailability of nanoparticulated DOX-MTX compared to free DOX. Moreover, in treated groups, tumor stage was markedly related to the amount of p53 mRNA (p<0.05). Conclusion: Both oral and IV application of our novel nanodrug possesses superior activity over free DOX-in up-regulation of p53 in a OSCC model and this increase in p53 level associated with less aggressive tumors in our study. Although, impressive results obtained with IV form of nanodrug (-21 fold increase in p53 mRNA level) but both forms of nanodrug are effective in OSCC, with less toxicity normal cells.

Keywords

p53;DOX-MTX-NPs;oral squamous cell carcinoma;oral and IV route;rat model

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