title: Oral and IV dosages of doxorubicin-methotrexate loaded- nanoparticles inhibit progression of oral cancer by down- regulation of matrix Methaloproteinase 2 expression in vivo.
abstract: Oral cancer is one of the most common and lethal cancers in the world. Combination chemotherapy coupled with nanoparticle drug delivery holds substantial promise in cancer therapy. This study aimed to evaluate the efficacy and safety of two dosages of our novel pH and temperature sensitive doxorubicin-methotrexate-loaded nanoparticles (DOX-MTX NPs) with attention to the MMP-2 mRNA profile in a 4-nitroquinoline-1-oxide induced oral squamous cell carcinoma (OSCC) model in the rat. Our results showed that both IV and oral dosages of DOX-MTX NP caused significant decrease in mRNA levels of MMP-2 compared to the untreated group (p<0.003). Surprisingly, MMP-2 mRNA was not affected in DOX treated compared to cancer group (p>0.05). Our results indicated that IV dosage of MTX-DOX is more effective than free DOX (12 fold) in inhibiting the activity of MMP-2 in OSCCs (P<0.001). Furthermore, MMP-2 mRNA expression in the DOX-MTX treated group showed a significant relation with histopathological changes (P=0.011). Compared to the untreated cancer group, we observed no pathological changes and neither a significant alteration in MMP-2 amount in either of healthy controls that were treated with oral and IV dosages of DOX-MTX NPs whilst cancer group showed a high level of MMP-2 expression compared to healthy controls (p<0.001).Taking together our results indicate that DOX- MTX NPs is a safe chemotherapeutic nanodrug that its oral and IV forms possess potent anti-cancer properties on aggressive tumors like OSCC, possibly by affecting the expression of genes that drive tumor invasion and metastasis.
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: Rana
authors.initials: R
authors.lastname: Jahanban-Esfahlan
authors.forename: Amir
authors.initials: A
authors.lastname: Monfaredan
authors.forename: Khaled
authors.initials: K
authors.lastname: Seidi
authors.forename: Hamed
authors.initials: H
authors.lastname: Hamishehkar
authors.forename: Monir Moradzadeh
authors.initials: MM
authors.lastname: Khiavi
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D000284:Administration, Oral; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D008727:Methotrexate / Q000008:administration & dosage; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D053758:Nanoparticles / Q000008:administration & dosage*; D015363:Quinolones / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C120195:4-nitroquinolone-1-oxide; D015363:Quinolones; D012333:RNA, Messenger; D015112:4-Nitroquinoline-1-oxide; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D008727:Methotrexate