title: Novel DOX-MTX nanoparticles improve oral SCC clinical outcome by down regulation of lymph dissemination factor VEGF-C expression in vivo: oral and IV 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. The aim of present study was to evaluate the efficacy of novel pH and temperature sensitive doxorubicin-methotrexate- loaded nanoparticles (DOX-MTX NP) in terms of their potential to change the VEGF-C expression profile in a rat OSCC model.
  
  
  METHODS
  120 male rats were divided into 8 groups of 15 animals administrated with 4-nitroquinoline-1-oxide to induce OSCCs. Newly formulated doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NP) and free doxorubicin were IV and orally administered.
  
  
  RESULTS
  RESULTS indicated that both oral and IV forms of DOX-MTX- nanoparticle complexes caused significant decrease in the mRNA level of VEGF-C compared to untreated cancerous rats (p<0.05) . Surprisingly, the VEGF-C mRNA was not affected by free DOX in both IV and oral modalities (p>0.05). Furthermore, in DOX-MTX NP treated group, less tumors characterized with advanced stage and VEGF-C mRNA level paralleled with improved clinical outcome (p<0.05). In addition, compared to untreated healthy rats , the VEGF-C expression was not affected in healthy groups that were treated with IV and oral dosages of nanodrug (p>0.05).
  
  
  CONCLUSIONS
  VEGF-C is one of the main prognosticators for lymph node metastasis in OSCC. Down-regulation of this lymph-angiogenesis promoting factor is a new feature acquired in group treated with dual action DOX-MTX-NPs. Beside the synergic apoptotic properties of concomitant use of DOX and MTX on OSCC, DOX-MTX NPs possessed anti-angiogenesis properties which was related to the improved clinical outcome in treated rats. Taking together, we conclude that our multifunctional doxorubicin-methotrexate complex exerts specific potent apoptotic and anti-angiogenesis properties that could ameliorate the clinical outcome presumably via down-regulating dissemination factor-VEGF-C expression in a rat OSCC model.
authors.affiliation: Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran E-mail : jahanbanr@tbzmed.ac.ir.
authors.forename: Mehran Mesgari
authors.initials: MM
authors.lastname: Abbasi
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: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002273:Carcinogens / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D015536:Down-Regulation; D004317:Doxorubicin / Q000008:administration & dosage; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053758:Nanoparticles / Q000737:chemistry*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042582:Vascular Endothelial Growth Factor C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D002273:Carcinogens; D012333:RNA, Messenger; D042582:Vascular Endothelial Growth Factor C; D015112:4-Nitroquinoline-1-oxide; D004317:Doxorubicin; D008727:Methotrexate