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Oral and IV Dosages of Doxorubicin-Methotrexate loaded-Nanoparticles Inhibit Progression of Oral Cancer by Down-Regulation of Matrix Methaloproteinase 2 Expression in Vivo

  • Abbasi, Mehran Mesgari (Drug Applied Research Center, Tabriz University of Medical Sciences) ;
  • Jahanban-Esfahlan, Rana (Student Research Committee, Tabriz University of Medical Sciences) ;
  • Monfaredan, Amir (Department of Hematology, Faculty of Medicine, Tabriz branch, Islamic Azad University) ;
  • Seidi, Khaled (Student Research Committee, Tabriz University of Medical Sciences) ;
  • Hamishehkar, Hamed (Drug Applied Research Center, Tabriz University of Medical Sciences) ;
  • Khiavi, Monir Moradzadeh (Department of Oral Pathology, Faculty of Dentistry, Tehran University of Medical Sciences, International Campus)
  • Published : 2015.01.22

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.

References

  1. Albano PM, Lumang-Salvador C, Orosa J 3rd, et al (2013). Overall survival of Filipino patients with squamous cell carcinoma of the head and neck: a single-institution experience. Asian Pac J Cancer Prev, 14, 4769-74. https://doi.org/10.7314/APJCP.2013.14.8.4769
  2. Albright CF, Graciani N, Han W, et al (2005). Matrix metalloproteinase-activated doxorubicin prodrugs inhibit HT1080 xenograft growth better than doxorubicin with less toxicity. Mol Cancer Ther, 4, 751-60. https://doi.org/10.1158/1535-7163.MCT-05-0006
  3. Bae Y (2010). Drug delivery systems using polymer nanoassemblies for cancer treatment. Ther Deliv, 1, 361-3. https://doi.org/10.4155/tde.10.28
  4. Baykara M, Buyukberber S, Ozturk B, et al (2013). Efficacy and safety of concomitant chemoradiotherapy with cisplatin and docetaxel in patients with locally advanced squamous cell head and neck cancers. Asian Pac J Cancer Prev, 14, 2557-61. https://doi.org/10.7314/APJCP.2013.14.4.2557
  5. Bell R, Kademani D, Homer L, et al (2007). Tongue cancer: Is there a difference in survival compared with other subsites in the oral cavity? J Oral Maxillofac Surg, 65, 229-36. https://doi.org/10.1016/j.joms.2005.11.094
  6. Benival D, PV D (2012). Lipomer of doxorubicin hydrochloride for enhanced oral bioavailability. Int J Pharm, 423, 554-61. https://doi.org/10.1016/j.ijpharm.2011.11.035
  7. Brandwein-Gensler M, Teixeira MS, Lewis CM, et al (2005). Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol, 29, 167-78. https://doi.org/10.1097/01.pas.0000149687.90710.21
  8. Chen Y, Wan Y, Wang Y, et al (2011). Anticancer efficacy enhancement and attenuation of side effects of doxorubicin with titanium dioxide nanoparticles. Int J Nanomedicine, 6, 2321-6.
  9. Cipriani P, Ruscitti P, Carubbi F, et al (2014). Methotrexate in Rheumatoid Arthritis: Optimizing Therapy Among Different Formulations. Current and Emerging Paradigms. ClinTher, 36, 427-35.
  10. Deng Y, Zhang H (2013). The synergistic effect and mechanism of doxorubicin-ZnO nanocomplexes as a multimodal agent integrating diverse anticancer therapeutics. Int J Nanomedicine, 8, 1835-41.
  11. Duong HH, Yung LY (2013). Synergistic co-delivery of doxorubicin and paclitaxel using multi-functional micelles for cancer treatment. Int J Pharm, 454, 486-95. https://doi.org/10.1016/j.ijpharm.2013.06.017
  12. Guhagarkar SA, Gaikwad RV, Samad A, et al (2010). Polyethylene sebacate-doxorubicin nanoparticles for hepatic targeting. Int J Pharm, 401, 113-22. https://doi.org/10.1016/j.ijpharm.2010.09.012
  13. Hong SD, Hong SP, Lee JI, et al (2000). Expression of matrix metalloproteinase-2 and -9 in oral squamous cell carcinomas with regard to the metastatic potential. Oral Oncol, 36, 207-13. https://doi.org/10.1016/S1368-8375(99)00088-3
  14. Hu Z, Jiang X Fau - Albright CF, Albright Cf Fau - Graciani N, et al (2010). Discovery of matrix metalloproteases selective and activated peptide-doxorubicin prodrugs as anti-tumor agents. Bioorg Med Chem Lett, 20, 853-6. https://doi.org/10.1016/j.bmcl.2009.12.084
  15. Huang WY, Yang PM, Chang YF, et al (2011). Methotrexate induces apoptosis through p53/p21-dependent pathway and increases E-cadherin expression through downregulation of HDAC/EZH2. Biochem Pharmacol, 81, 510-7. https://doi.org/10.1016/j.bcp.2010.11.014
  16. Jahanban Esfahlan R, Zarghami N, Jahanban Esfahlan A, et al (2011a). The possible impact of obesity on androgen, progesterone and estrogen receptors (ERa and ERb) gene expression in breast cancer patients. Breast Cancer, 5, 227-37.
  17. Jahanban Esfahlan R, Zarghami N, Rahmati-Yamchi M, et al (2011b). Quantification of steroid receptors gene expression in breast cancer patients: possible correlation with serum level of adipocytokines. J Cancer Therapy, 2, 659-65. https://doi.org/10.4236/jct.2011.25088
  18. Jahanban Esfahlan R, Zarghami N, Valiyari S, et al (2012). Adiponectin Can Affect ER Signaling in Obese Breast Cancer Patients. J Cancer Therapy, 3, 115-21 https://doi.org/10.4236/jct.2012.31015
  19. Jain S, Patil SR, Swarnakar NK, et al (2012). Oral delivery of doxorubicin using novel polyelectrolyte-stabilized liposomes (layersomes). Mol Pharm, 9, 2626-35. https://doi.org/10.1021/mp300202c
  20. Jones KR, Lodge-Rigal RD, Reddick RL, et al (1992). Prognostic factors in the recurrence of stage I and II squamous cell cancer of the oral cavity. Arch Otolaryngol Head Neck Surg, 118, 483-5. https://doi.org/10.1001/archotol.1992.01880050029006
  21. Kademani D, Bell RB, Bagheri S, et al (2005). Prognostic factors in intraoral squamous cell carcinoma: the influence of histologic grade. J Oral Maxillofac Surg, 63, 1599-605. https://doi.org/10.1016/j.joms.2005.07.011
  22. Kalaria DR, Sharma G, Beniwal V, et al (2009). Design of biodegradable nanoparticles for oral delivery of doxorubicin: in vivo pharmacokinetics and toxicity studies in rats. Pharm Res, 26, 492-501. https://doi.org/10.1007/s11095-008-9763-4
  23. Liboiron B, Mayer L (2014). Nanoscale particulate systems for multidrug delivery: towards improved combination chemotherapy. Ther Deliv, 5, 149-71. https://doi.org/10.4155/tde.13.149
  24. Lin CW, Chen PN, Chen MK, et al (2013). Kaempferol reduces matrix metalloproteinase-2 expression by down-regulating ERK1/2 and the activator protein-1 signaling pathways in oral cancer cells. PLoS.One, 8, 80883. https://doi.org/10.1371/journal.pone.0080883
  25. Lippman SM, Hong WK (2001). Molecular markers of the risk of oral cancer. N Engl J Med, 344, 1323-6. https://doi.org/10.1056/NEJM200104263441710
  26. Massano J, Regateiro FS, Januario G, et al (2006). Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 102, 67-76. https://doi.org/10.1016/j.tripleo.2005.07.038
  27. Mehdipour M, Taghavi ZA, Mesgari AM, et al (2013). Evaluation of the effect of two systemic doses of HESA-A on prevention of induced tongue neoplasm in rats. J Dent Res Dent Clin Dent Prospects, 7, 218-24.
  28. Mesgari Abbasi M, Monfaredan A, Hamishehkar H, et al (2014a). DOX-MTX-NPs augment p53 mRNA expression in OSCCs model in rat: the effect of IV and oral dosages Asian Pac J Cancer Prev, 15, 8377-82. https://doi.org/10.7314/APJCP.2014.15.19.8377
  29. Mesgari Abbasi M, Monfaredan A, Hamishehkar H, et al (2014b). 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. Asian Pac J Cancer Prev, 15, 6227-32. https://doi.org/10.7314/APJCP.2014.15.15.6227
  30. Montoro JR, Ricz HA, Souza L, et al (2008). Prognostic factors in squamous cell carcinoma of the oral cavity. Braz J Otorhinolaryngol, 74, 861-6. https://doi.org/10.1016/S1808-8694(15)30146-4
  31. Nasiri M, Zarghami N, Nejati Koshki K, et al (2013). Curcumin and silibinin inhibit telomerase expression in T47D human breast cancer cells. Asian Pac J Cancer Prev, 14, 3449-53 https://doi.org/10.7314/APJCP.2013.14.6.3449
  32. Pardis S, Sardari Y, Ashraf MJ, et al (2012). Evaluation of tissue expression and salivary levels of HER2/neu in patients with head and neck squamous cell carcinoma. Iran J Otorhinolaryngol, 24, 161-70.
  33. Rossi B, Schinzari G, Maccauro G, et al (2010). Neoadjuvant multidrug chemotherapy including high-dose methotrexate modifies VEGF expression in osteosarcoma: an immunohistochemical analysis. BMC Musculoskelet Disord, 11, 34. https://doi.org/10.1186/1471-2474-11-34
  34. Rusthoven KE, Raben D, Song JI, et al (2010). Survival and patterns of relapse in patients with oral tongue cancer. J Oral Maxillofac Surg, 68, 584-9. https://doi.org/10.1016/j.joms.2009.03.056
  35. Salehi R, Hamishehkar H, Eskandani M, et al (2014). Development of dual responsive nanocomposite for simultaneous delivery of anticancer drugs. J Drug Target, 22, 327-42. https://doi.org/10.3109/1061186X.2013.876645
  36. Schliephake H (2003). Prognostic relevance of molecular markers of oral cancer--a review. Int J Oral Maxillofac Surg, 32, 233-45. https://doi.org/10.1054/ijom.2002.0383
  37. Sharma P, Shah SV, Taneja C, et al (2013). A prospective study of prognostic factors for recurrence in early oral tongue cancer. J Clin Diagn Res, 7, 2559-62.
  38. Tacar O, Sriamornsak P, Dass CR (2013). Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharmacol, 65, 157-70. https://doi.org/10.1111/j.2042-7158.2012.01567.x
  39. Thomas GT, Lewis MP, Speight PM (1999). Matrix metalloproteinases and oral cancer. Oral Oncol, 35, 227-33. https://doi.org/10.1016/S1368-8375(99)00004-4
  40. Valiyari S, Jahanban-Esfahlan R, Zare Shahneh F, et al (2013). Cytotoxic and apoptotic activity of Scrophularia oxysepala in MCF-7 human breast cancer cells. Toxicol Environmental Chem, 95, 1208-20. https://doi.org/10.1080/02772248.2013.854362
  41. Vilen ST, Salo T, Sorsa T, et al (2013). Fluctuating roles of matrix metalloproteinase-9 in oral squamous cell carcinoma. ScientificWorld J, 2013, 920595.
  42. Wang Y, Wei X, Zhang C, et al (2010). Nanoparticle delivery strategies to target doxorubicin to tumor cells and reduce side effects. Ther Deliv, 1, 273-87. https://doi.org/10.4155/tde.10.24
  43. Yoo HS, Park TG (2004). Folate-receptor-targeted delivery of doxorubicin nano-aggregates stabilized by doxorubicin-PEG-folate conjugate. J Control Release, 100, 247-56. https://doi.org/10.1016/j.jconrel.2004.08.017
  44. Zwetyenga N, Majoufre-Lefebvre C, Siberchicot F, et al (2003). [Squamous-cell carcinoma of the tongue: treatment results and prognosis]. Rev.Stomatol. Chir Maxillofac, 104, 10-7.

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