title: DOX-MTX-NPs augment p53 mRNA expression in OSCC model in rat: effects of IV and oral routes.
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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Drug Applied Research Center, Tabriz, Iran E-mail : jahanbanr@tbzmed.ac.ir.
authors.forename: Mehran Mesgari
authors.initials: MM
authors.lastname: Abbasi
authors.forename: Monir Moradzadeh
authors.initials: MM
authors.lastname: Khiavi
authors.forename: Amir
authors.initials: A
authors.lastname: Monfaredan
authors.forename: Hamed
authors.initials: H
authors.lastname: Hamishehkar
authors.forename: Khaled
authors.initials: K
authors.lastname: Seidi
authors.forename: Rana
authors.initials: R
authors.lastname: Jahanban-Esfahlan
mesh_terms: D000283:Administration, Intravesical; D000284:Administration, Oral; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D004333:Drug Administration Routes; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000494:pharmacology; D009062:Mouth Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D053758:Nanoparticles; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D008727:Methotrexate