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Novel Fish Oil-based Bigel System for Controlled Drug Delivery and its Influence on Immunomodulatory Activity of Imiquimod Against Skin Cancer

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Abstract

Purpose

To characterize bigel system as a topical drug delivery vehicle and to establish the immunomodulatory role of imiquimod-fish oil combination against skin cancer and inflammation resulting from chemical carcinogenesis.

Methods

Imiquimod-loaded fish oil bigel colloidal system was prepared using a blend of carbopol hydrogel and fish oil oleogel. Bigels were first characterized for their mechanical properties and compared to conventional gel systems. Ex vivo permeation studies were performed on murine skin to analyze the ability of the bigels to transport drug across skin and to predict the release mechanism via mathematical modelling. Furthermore, to analyze pharmacological effectiveness in skin cancer and controlling imiquimod-induced inflammatory side effects, imiquimod-fish oil combination was tested in vitro on epidermoid carcinoma cells and in vivo in Swiss albino mice cancer model.

Results

Imiquimod-loaded fish oil bigels exhibited higher drug availability inside the skin as compared to individual imiquimod hydrogel and oleogel controls through quasi-Fickian diffusion mechanism. Imiquimod-fish oil combination in bigel enhanced the antitumor effects and significantly reduced serum pro-inflammatory cytokine levels such as tumor necrosis factor-alpha and interleukin-6, and reducing tumor progression via inhibition of vascular endothelial growth factor. Imiquimod-fish oil combination also resulted in increased expression of interleukin-10, an anti-inflammatory cytokine, which could also aid anti-tumor activity against skin cancer.

Conclusion

Imiquimod administration through a bigel vehicle along with fish oil could be beneficial for controlling imiquimod-induced inflammatory side effects and in the treatment of skin cancer.

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Abbreviations

HPV:

Human papilloma virus

EPA:

Eicosapentaenoic acid

DHA:

Docosahexaenoic acid

VEGF:

Vascular endothelial growth factor

ELISA:

Enzyme-linked immunosorbent assays

IL:

Interleukin

TNF:

Tumor necrosis factor

FO:

Fish oil

IMQ:

Imiquimod

IMQ-FO:

Imiquimod-fish oil

PBS:

Phosphate buffer solution

SC:

Stratum corneum

EPD:

Epidermis and dermis

DMBA:

7,12-dimethylbenz(a)anthracene

IFN:

Interferon

REFERENCES

  1. Leibovitch I, Huilgol SC, Selva D, Hill S, Richards S, Paver R. Cutaneous squamous cell carcinoma treated with mohs micrographic surgery in Australia I. Experience over 10 years. J Am Acad Dermatol. 2005;53:253–60.

    Article  PubMed  Google Scholar 

  2. Rogers HW, Weinstock MA, Harris AR. Incidence estimate of nonmelanoma skin cancer of the United States. Arch Dermatol. 2005;146:283–7.

    Google Scholar 

  3. Johnson TM, Rowe DE, Nelson BR, Swanson NA. Squamous cell carcinoma of the skin (excluding lip and oral mucosa), Journal of the American Academy of Dermatology. J Am Acad Dermatol. 1992;26:467–84.

    Article  CAS  PubMed  Google Scholar 

  4. Vivek VG, Eric MG. Cutaneous squamous cell carcinoma of the head and neck. J Skin Cancer. 2011;2011:3–13.

    Google Scholar 

  5. Teicher BA, Ara G, Buxton D, Leonard J, Schaub RG. Optimal scheduling of interleukin-12 and chemotherapy in the murine MB-49 bladder carcinoma and B-16 melanoma. Clin Cancer Res. 1997;3:1661–7.

    CAS  PubMed  Google Scholar 

  6. Graells J, Ojeda RM, Garcia-Cruz A. Effect of imiquimod as compared with surgery on the cancerization field in basal cell carcinoma. Actas Dermosifiliogr. 2014;105:53–9.

    Article  CAS  PubMed  Google Scholar 

  7. Tarbet EB, Larson D, AB J, Bailey KW, Wong MH Smee DF. Evaluation of imiquimod for topical treatment of vaccinia virus cutaneous infections in immunosuppressed hairless mice. Antiviral Res. 2011;90:126–33.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Jin JY, Jung YJ, Choi S, Hwang J, Chung E. Autophagy mediated anti-tumoral of imiquimod in CaCo-2 cells. Biochem Biophys Res Commun. 2009;386:455–8.

    Article  Google Scholar 

  9. Hadley G, Derry S, Moore RA. Imiquimod for actinic keratosis: systematic review and meta-analysis. J Investig Dermatol. 2006;126:1251–5.

    Article  CAS  PubMed  Google Scholar 

  10. Cantisani C, Lazic T, Richetta AG, Clerico R, Mattozzi C, Calvieri S. Imiquimod 5% cream use in dermatology, side effects and recent patents. Recent Patents Inflamm Allergy Drug Discov. 2012;6(1):65–9.

    Article  CAS  Google Scholar 

  11. Rosenblatt A. Campos GHGd. Local and systemic adverse effects of imiquimod therapy for external anogenital warts in men: report of three cases. Int J STD AIDS. 2012;23:909–10.

    Article  CAS  PubMed  Google Scholar 

  12. Rehman K, Aluwi MFFM, Rullah K, Wai LK, Amin MCIM, Zulfakar MH. Probing the effects of fish oil on the delivery and inflammation-inducing potential of imiquimod. Int J Pharm. 2015;490:131–41.

    Article  CAS  PubMed  Google Scholar 

  13. Kadir R, Stempler D, Liron Z, Cohen S. Delivery of theophylline into excised human skin from alkanoic acid solutions: a “push-pull” mechanism. J Pharm Sci. 1987;76:774–9.

    Article  CAS  PubMed  Google Scholar 

  14. Chirstopher PT, Jamie P, Thomas T, Heard MC. Probing the skin permeation of fish oil/EPA and ketoprofen: 1. NMR spectroscopy and molecular modelling. Int J Pharm. 2007;338:207–12.

    Article  Google Scholar 

  15. Almedia IF, Fernandes AR, Fernandes L, Ferreira MRP, Costa PC, Bahia MF. Moisturizing effect of oleogel/hydrogel mixtures. Pharm Dev Technol. 2008;13:487–94.

    Article  Google Scholar 

  16. Rhee GJ, Woo JS, Hwang SJ, Lee YW, Lee CH. Topical oleo-hydrogel preparation of ketoprofen with enhanced skin permeability. Drug Dev Ind Pharm. 1999;25:717–26.

    Article  CAS  PubMed  Google Scholar 

  17. Vinay KS, Indranil B, Tarun A, Krishna P, Mrinal KB, Kunal P. Guar gum and sesame oil based novel bigels for controlled drug delivery. Colloids Surf B: Biointerfaces. 2014;123:582–92.

    Article  Google Scholar 

  18. Rehman K, Zulfakar MH. Recent advances in gel technologies for topical and transdermal drug delivery. Drug Dev Ind Pharm. 2014;40(4):433–40.

    Article  CAS  PubMed  Google Scholar 

  19. Zulfakar MH, Abdelouahab N, Heard MC. Enhanced topical delivery and ex vivo anti-inflammatory activity from a betamethasone dipropionate formulation containing fish oil. Inflamm Res. 2010;59:23–30.

    Article  CAS  PubMed  Google Scholar 

  20. Chirstopher PT, Heard MC. Probing the skin permeation of eicosapentaenoic acid and ketoprofen 2. Comparative depth profiling and metabolism of eicospentaenoic acid. Eur J Pharm Biopharm. 2007;67:156–65.

    Article  Google Scholar 

  21. Huri MFD, Ng SF, Zulfakar MH. Fish oil-based oleogels: physicochemicals characterisation and invitro release of betemethasone dipropionate. Int J Pharm Pharm Sci. 2013;5:458–67.

    Google Scholar 

  22. Rehman K, Tan CM, Zulfakar MH. Development and in-vitro characterization of fish oil oleogels containing benzoyl peroxide and salicylic acid as keratolytic agents. Adv Drug Res. 2014;64:159–65.

    CAS  Google Scholar 

  23. Nugteren DH, Hazelhof CE. Van dbA, Houtsmuller UMT. Metabolism of linoleic acid and other essential fatty acids in the epidermis of the rat. Biochim Biophys Acta. 1995;834:429–36.

    Article  Google Scholar 

  24. Lademann J, Jacobi U, Surber C, Weigmann HJ, Fluhr JW. The tape stripping procedure--evaluation of some critical parameters. Eur J Pharm Biopharm. 2009;72(2):317–23.

    Article  CAS  PubMed  Google Scholar 

  25. Coderch L, Oliva M, Pons M, Maza ADI, Manich AM, Parra JL. Percutaneous penetration of liposomes using the tape stripping technique. Int J Pharm. 1996;139:197–203.

    Article  CAS  Google Scholar 

  26. Paula DD, Martins CA, Bentley MV. Development and validation of HPLC method for imiquimod determination in skin penetration studies. Biomed Chromatogr. 2008;22:1416–23.

    Article  PubMed  Google Scholar 

  27. Rohrbach R, Iversen OH, Riede UN, Sandritter W. Effects of cellophane tape stripping of mouse skin on epidermal growth regulators (chalones). Beitr Pathol. 1977;160:175–86.

    Article  CAS  PubMed  Google Scholar 

  28. Xiaolu L, Johanthan E, Rajendra S, Chenlu M, Krystyna F. Interleukin-1α Up-Regulation in Vivo by a Potent Carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and Control of DMBA-induced Inflammatory Responses. Cancer Res. 2002;62:417–23.

    Google Scholar 

  29. Ko JH, Jung YS, Lee BJ. Inhibitory effects of interferon-gamma plasmid DNA on DMBA-TPA induced mouse skin carcinogenesis. Cancer Gene Ther. 2011;18:646–54.

    Article  CAS  PubMed  Google Scholar 

  30. Hussain Z, Katas H, Amin MCIM, Endang K. Efficient immuno-modulation of TH1/TH2 biomarkers in 2,4 dinitroflurobenzene induced atopic dermatits: Nanocarrier mediated transcutaneous co-delivery of anti-inflammatory and antioxidant drugs. Plos One. 2014;9:1–17.

    Google Scholar 

  31. Orbach R, Gurevich M, Achiron A. Interleukin-12p40 in the spinal fluid as a biomarker for clinically isolated syndrome. Multiple Sclerosis J. 2014;20(1):35–42.

    Article  CAS  Google Scholar 

  32. Kemeny L. Non-surgical treatment of keratinocyte skin cancer. Berlin-Heidelberg: Springer; 2010.

    Google Scholar 

  33. Li VW, Li WW, Talcott KE. Imiquimod as an antiangiogenic agent. J Drug Dermatol. 2005;4:708–17.

    Google Scholar 

  34. Gabriella C, Fiorella DN, Simona G, Elisabetta P, Simona S, Nicola M, et al. n-3 PUFAs reduce VEGF expression in human cancer cells modulating the COX-2/PGE2 Induced ERK-1 and −2 and HIF-1alpha induction pathway. Carcinogenesis. 2004;25:2303–10.

    Article  Google Scholar 

  35. Kelly EJ, Traci AW. Multiple roles of VEGF in non-melanoma skin cancer: angiogenesis and beyond. J Skin Cancer. 2012;2012:1–6.

    Google Scholar 

  36. Wu Y, Zhou BP. TNF-α/NF-kB/Snail pathway in cancer migration and invasion. Br J Cancer. 2010;102:639–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fiorella G, Patrizia F, Raffaele P, Ilaria P, Vincenzo F, Mario R. TNF/VEGF cross-talk in chronic inflammation-related cancer initiation and progression: an early target in anticancer therapeutic strategy. In vivo. 2007;21:147–62.

    Google Scholar 

  38. Neil AT, Romana SM, Philip W, David JOR, Stephen GB, Karen EP. Mechanism of TNF-α -induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones. Cardiovasc Res. 2007;76:81–90.

    Article  Google Scholar 

  39. Kumiko T, Rie MN, Shinobu Y, Hiroki L, Shuji D, Osamu K. Mechanisms of tumor necrosis factor-a-inducd interleukin-6 synthesis in glioma cells. J Neuroinflammation. 2010;7:16–24.

    Article  Google Scholar 

  40. Lederle W, Depner S, Schnur S, Obermueller E, Catone N, Just A, et al. IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines. Int J Cancer. 2011;128:2803–14.

    Article  CAS  PubMed  Google Scholar 

  41. Shiou-Hwa J, Shing-Chuan S, Hsien-Ching C, Wei-Ling T, Kuo ML. Overexpression of interleukin-6 in human basal cell carcinoma cell lines increases anti-apoptotic activity and tumorigenic potency. Oncogene. 2001;20:198–202.

    Article  Google Scholar 

  42. Michele WLT, Philip KD, Mark JS. Stable IL10: a new therapeutic that promotes tumor immunity. Cancer Cell. 2011;20:691–3.

    Article  Google Scholar 

  43. Karin L, Jenny A, Maik V, Marietter M, Sandra B, Thomas S, et al. IL10 controls ultraviolet-induced carcinogenesis in mice. J Immunol. 2007;179:365–71.

    Article  Google Scholar 

  44. Anke J, Michael W, Bernhard W, Christina N, Alexander R, Alfered L, et al. Evaluation of suppressive and pro-resolving effects of EPA and DHA in human primary monocytes and T-helper cells. J Lipid Res. 2013;54:923–35.

    Article  Google Scholar 

  45. Yone VNC, Maria CAB, Juliana KDALN, Jose CF, Valeria RAP. Role of TNF-alpha, IFN-gamma, and IL-10 in development of pulmonary tuberculosis. Pulmonary Med. 2012;2012:1–10.

    Google Scholar 

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ACKNOWLEDGMENTS AND DISCLOSURES

The authors would like to thank the Ministry of Education, Malaysia for providing research grant ERGS/1/2013/SKK02/UKM/02/3, and Faculty of Pharmacy, Universiti Kebangsaan Malaysia for additional support during this study.

Authors have no conflict of interest to report.

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Authors and Affiliations

  1. Lahore Pharmacy College (A Project of Lahore Medical and Dental College), Tulspura Canal Bank, Lahore, 53400, Pakistan

    Khurram Rehman

  2. Centre for Drug Delivery Research, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300, Kuala Lumpur, Malaysia

    Khurram Rehman & Mohd Hanif Zulfakar

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  1. Khurram Rehman
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Correspondence to Mohd Hanif Zulfakar.

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Rehman, K., Zulfakar, M.H. Novel Fish Oil-based Bigel System for Controlled Drug Delivery and its Influence on Immunomodulatory Activity of Imiquimod Against Skin Cancer. Pharm Res 34, 36–48 (2017). https://doi.org/10.1007/s11095-016-2036-8

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  • DOI: https://doi.org/10.1007/s11095-016-2036-8

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