Abstract
Melanoma is a potentially lethal skin cancer with high mortality rate. Recently, the peptide-mediated transdermal delivery of small interference RNA (siRNA) emerges as a promising strategy to treat melanoma by inducing the apoptosis of tumor cells, but the related theoretical model describing the delivery of siRNA under the effect of SPACE-EGF, the growth inhibition of melanoma and the dynamic expanding of the bump on the skin due to the growth of melanoma has not been reported yet. In this article, a theoretical model is developed to describe the percutaneous siRNA delivery mediated by SPACE-EGF to melanoma and the growth inhibition of melanoma. The results present the spatial–temporal distribution of siRNA and the growth of melanoma under the inhibition of siRNA, which shows a good consistency with the experimental results. In addition, this model represents the uplift process of tumors on the skin surface. The model presented here is a useful tool to understand the whole process of the SPACE-EGF-mediated delivery of the siRNA to melanoma through skin, to predict the therapeutic effect, and to optimize the therapeutic strategy, providing valuable references for the treatment of melanoma.
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References
Adam, J. A. A simplified mathematical-model of tumor-growth. Math. Biosci. 81:229–244, 1986.
Ahn, J.-H., and M. Lee. The siRNA-mediated downregulation of N-Ras sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors. Mol. Cell. Biochem. 392:239–247, 2014.
Bartlett, D. W., and M. E. Davis. Insights into the kinetics of siRNA-mediated gene silencing from live-cell and live-animal bioluminescent imaging. Nucleic Acids Res. 34:322–333, 2006.
Bartlett, D. W., H. Su, I. J. Hildebrandt, W. A. Weber, and M. E. Davis. Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging. Proc. Natl. Acad. Sci. USA 104:15549–15554, 2007.
Bentele, M., I. Lavrik, M. Ulrich, S. Stosser, D. W. Heermann, H. Kalthoff, P. H. Krammer, and R. Eils. Mathematical modeling reveals threshold mechanism in CD95-induced apoptosis. J. Cell Biol. 166:839–851, 2004.
Bernardo, F. P., and P. M. Saraiva. A theoretical model for transdermal drug delivery from emulsions and its dependence upon formulation. J. Pharm. Sci. 97:3781–3809, 2008.
Busini, V., P. Arosio, and M. Masi. Mechanistic modelling of avascular tumor growth and pharmacokinetics influence: part I. Chem. Eng. Sci. 62:1877–1886, 2007.
Byrne, H. M., and M. A. J. Chaplain. Growth of necrotic tumors in the presence and absence of inhibitors. Math. Biosci. 135:187–216, 1996.
Byrne, H., and L. Preziosi. Modelling solid tumour growth using the theory of mixtures. Math. Med. Biol. 20:341–366, 2003.
Chandrasekaran, S., A. Michaels, P. Campbell, and J. Shaw. Scopolamine permation through human skin in vitro. AIChE J. 22:828–832, 1976.
Chen, Y., S. R. Bathula, Q. Yang, and L. Huang. Targeted nanoparticles deliver siRNA to melanoma. J. Investig. Dermatol. 130:2790–2798, 2010.
Chen, M., S. Kumar, A. C. Anselmo, V. Gupta, D. H. Slee, J. A. Muraski, and S. Mitragotri. Topical delivery of cyclosporine A into the skin using SPACE-peptide. J. Control. Release 199:190–197, 2015.
Chen, Y., Y. Shen, X. Guo, C. Zhang, W. Yang, M. Ma, S. Liu, M. Zhang, and L.-P. Wen. Transdermal protein delivery by a coadministered peptide identified via phage display. Nat. Biotechnol. 24:455–460, 2006.
Chen, M., M. Zakrewsky, V. Gupta, A. C. Anselmo, D. H. Slee, J. A. Muraski, and S. Mitragotri. Topical delivery of siRNA into skin using SPACE-peptide carriers. J. Control. Release 179:33–41, 2014.
Desai, P. R., S. Marepally, A. R. Patel, C. Voshavar, A. Chaudhuri, and M. Singh. Topical delivery of anti-TNFα siRNA and capsaicin via novel lipid-polymer hybrid nanoparticles efficiently inhibits skin inflammation in vivo. J. Control. Release 170:51–63, 2013.
Devi, G. R. siRNA-based approaches in cancer therapy. Cancer Gene Ther. 13:819–829, 2006.
Dikic, I. Mechanisms controlling EGF receptor endocytosis and degradation. Biochem. Soc. Trans. 31:1178–1181, 2003.
Eissing, T., H. Conzelmann, E. D. Gilles, F. Allgower, E. Bullinger, and P. Scheurich. Bistability analyses of a caspase activation model for receptor-induced apoptosis. J. Biol. Chem. 279:36892–36897, 2004.
Garcia, M., F. Larcher, R. P. Hickerson, E. Baselga, S. A. Leachman, R. L. Kaspar, and M. Del Rio. Development of skin-humanized mouse models of pachyonychia congenita. J. Investig. Dermatol. 131:1053–1060, 2011.
Godin, B., and E. Touitou. Transdermal skin delivery: predictions for humans from in vivo, ex vivo and animal models. Adv. Drug Deliv. Rev. 59:1152–1161, 2007.
Goodlett, C. R., and K. H. Horn. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res. Health 25:175–184, 2001.
Goodman, T. T., J. Chen, K. Matveev, and S. H. Pun. Spatio-temporal modeling of nanoparticle delivery to multicellular tumor spheroids. Biotechnol. Bioeng. 101:388–399, 2008.
Graff, C. P., and K. D. Wittrup. Theoretical analysis of antibody targeting of tumor spheroids importance of dosage for penetration, and affinity for retention. Can. Res. 63:1288–1296, 2003.
Gu, W., Z. Jia, N. P. Truong, I. Prasadam, Y. Xiao, and M. J. Monteiro. Polymer nanocarrier system for endosome escape and timed release of siRNA with complete gene silencing and cell death in cancer cells. Biomacromol 14:3386–3389, 2013.
Gu, W. Y., H. Yao, A. L. Vega, and D. Flagler. Diffusivity of ions in agarose gels and intervertebral disc: effect of porosity. Ann. Biomed. Eng. 32:1710–1717, 2004.
Hengge, U. R., E. F. Chan, R. A. Foster, P. S. Walker, and J. C. Vogel. Cytokine egne-expression in epidermis with biological effects following injection of naked DNA. Nat. Genet. 10:161–166, 1995.
Hong, J., Y. Zhao, and W. Huang. Blocking c-myc and stat3 by E. coli expressed and enzyme digested siRNA in mouse melanoma. Biochem. Biophys. Res. Commun. 348:600–605, 2006.
Hsu, T., and S. Mitragotri. Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc. Natl. Acad. Sci. USA 108:15816–15821, 2011.
Irrechukwu, O. N., and M. E. Levenston. Improved estimation of solute diffusivity through numerical analysis of FRAP experiments. Cell. Mol. Bioeng. 2:104–117, 2009.
Jemal, A., R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun. Cancer statistics, 2009. CA Cancer J. Clin. 59:225–249, 2009.
Kalia, Y. N., and R. H. Guy. Modeling transdermal drug release. Adv. Drug Deliv. Rev. 48:159–172, 2001.
Karande, P., A. Jain, and S. Mitragotri. Discovery of transdermal penetration enhancers by high-throughput screening. Nat. Biotechnol. 22:192–197, 2004.
Kim, K. S., K. Ita, and L. Simon. Modelling of dissolving microneedles for transdermal drug delivery: theoretical and experimental aspects. Eur. J. Pharm. Sci. 68:137–143, 2015.
Kiran, K. L., D. Jayachandran, and S. Lakshminarayanan. Mathematical modelling of avascular tumor growth based on diffusion of nutrients and its validation. Can. J. Chem. Eng. 87:732–740, 2009.
Kobayashi, D., T. Matsuzawa, K. Sugibayashi, Y. Morimoto, and M. Kimura. Analysis of the combined effect of 1-menthol and ethanol as skin permeation enhancers based on a two-layer skin model. Pharm. Res. 11:96–103, 1994.
Koizumi, T., M. Ueda, M. Kakemi, and H. Kameda. Rate of release of medicaments from ointment bases containing drugs in suspension. Chem. Pharm. Bull. 23:3288–3292, 1975.
Kretsos, K., G. B. Kasting, and J. M. Nitsche. Distributed diffusion–clearance model for transient drug distribution within the skin. J. Pharm. Sci. 93:2820–2835, 2004.
Kumar, S., M. Chen, A. C. Anselmo, J. A. Muraski, and S. Mitragotri. Enhanced epidermal localization of topically applied steroids using SPACE peptide. Drug Deliv. Transl. Res. 5:523–530, 2015.
Leachman, S. A., R. P. Hickerson, M. E. Schwartz, E. E. Bullough, S. L. Hutcherson, K. M. Boucher, C. D. Hansen, M. J. Eliason, G. S. Srivatsa, D. J. Kornbrust, F. J. D. Smith, W. H. I. McLean, L. M. Milstone, and R. L. Kaspar. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol. Ther. 18:442–446, 2010.
Lee, A. J., J. R. King, and D. A. Barrett. Percutaneous absorption: a multiple pathway model. J. Control. Release 45:141–151, 1997.
Lee, A. J., J. R. King, and T. G. Rogers. A multiple-pathway model for the diffusion of drugs in skin. IMA J. Math. Appl. Med. Biol. 13:127–150, 1996.
Li, S.-D., S. Chono, and L. Huang. Efficient oncogene silencing and metastasis inhibition via systemic delivery of siRNA. Mol. Ther. 16:942–946, 2008.
Macklin, P., and J. Lowengrub. Nonlinear simulation of the effect of microenvironment on tumor growth. J. Theor. Biol. 245:677–704, 2007.
Manitz, R., W. Lucht, K. Strehmel, R. Weiner, and R. Neubert. On mathematical modeling of dermal and transdermal drug delivery. J. Pharm. Sci. 87:873–879, 1998.
Márquez-Rodas, I., S. M. Algarra, J. A. A. Izquierdo, S. C. Cabello, and M. Martín. A new era in the treatment of melanoma: from biology to clinical practice. Clin. Transl. Oncol. 13:787–792, 2011.
Mccarley, K. D., and A. L. Bunge. Pharmacokinetic models of dermal absorption. J. Pharm. Sci. 90:1699–1719, 2001.
Mirmohammadsadegh, A., M. Hassan, A. Gustrau, R. Doroudi, N. Schmittner, S. Nambiar, A. Tannapfel, T. Ruzicka, and U. R. Hengge. Constitutive expression of epidermal growth factor receptors on normal human melanocytes. J. Investig. Dermatol. 125:392–394, 2005.
Norris, E. S., J. R. King, and H. M. Byrne. Modelling the response of spatially structured tumours to chemotherapy: drug kinetics. Math. Comput. Model. 43:820–837, 2006.
Prausnitz, M. R., and R. Langer. Transdermal drug delivery. Nat. Biotechnol. 26:1261–1268, 2008.
Rao, Y.-F., W. Chen, X.-G. Liang, Y.-Z. Huang, J. Miao, L. Liu, Y. Lou, X.-G. Zhang, B. Wang, R.-K. Tang, Z. Chen, and X.-Y. Lu. Epirubicin-loaded superparamagnetic iron-oxide nanoparticles for transdermal delivery: cancer therapy by circumventing the skin barrier. Small 11:239–247, 2015.
Rim, J. E., P. M. Pinsky, and W. W. van Osdol. Finite element modeling of coupled diffusion with partitioning in transdermal drug delivery. Ann. Biomed. Eng. 33:1422–1438, 2005.
Ruan, R., M. Chen, S. Sun, P. Wei, L. Zou, J. Liu, D. Gao, L. Wen, and W. Ding. Topical and targeted delivery of siRNAs to melanoma cells using a fusion peptide carrier. Scient. Rep. 6:29159, 2016.
Shenenberger, D. W. Cutaneous malignant melanoma: a primary care perspective. Am. Fam. Phys. 85:161–168, 2012.
Siu, K. S., D. Chen, X. Zheng, X. Zhang, N. Johnston, Y. Liu, K. Yuan, J. Koropatnick, E. R. Gillies, and W.-P. Min. Non-covalently functionalized single-walled carbon nanotube for topical siRNA delivery into melanoma. Biomaterials 35:3435–3442, 2014.
Sladden, M. J., C. Balch, D. A. Barzilai, D. Berg, A. Freiman, T. Handiside, S. Hollis, M. B. Lens, and J. F. Thompson. Surgical excision margins for primary cutaneous melanoma. Cochrane Database Syst. Rev. 2009. doi:10.1002/14651858.CD004835.pub2.
Snorradottir, B. S., F. Jonsdottir, S. T. Sigurdsson, and M. Masson. Numerical modelling of transdermal delivery from matrix systems: parametric study and experimental validation with silicone matrices. J. Pharm. Sci. 103:2366–2375, 2014.
Vizseralek, G., S. Berko, G. Toth, R. Balogh, M. Budai-Szucs, E. Csanyi, B. Sinko, and K. Takacs-Novak. Permeability test for transdermal and local therapeutic patches using skin PAMPA method. Eur. J. Pharm. Sci. 76:165–172, 2015.
Ward, J. P., and J. R. King. Mathematical modelling of avascular-tumour growth. IMA J. Math. Appl. Med. Biol. 14:39–69, 1997.
Weissberg, H. L. Effective diffusion coefficient in porous media. J. Appl. Phys. 34:2636–2639, 1963.
Yamashita, F., and M. Hashida. Mechanistic and empirical modeling of skin permeation of drugs. Adv. Drug Deliv. Rev. 55:1185–1199, 2003.
Zheng, D., D. A. Giljohann, D. L. Chen, M. D. Massich, X.-Q. Wang, H. Iordanov, C. A. Mirkin, and A. S. Paller. Topical delivery of siRNA-based spherical nucleic acid nanoparticle conjugates for gene regulation. Proc. Natl. Acad. Sci. USA 109:11975–11980, 2012.
Zhuang, D., S. Mannava, V. Grachtchouk, W. H. Tang, S. Patil, J. A. Wawrzyniak, A. E. Berman, T. J. Giordano, E. V. Prochownik, M. S. Soengas, and M. A. Nikiforov. C-MYC overexpression is required for continuous suppression of oncogene-induced senescence in melanoma cells. Oncogene 27:6623–6634, 2008.
Acknowledgment
This work was supported partly by the Specialized Research Fund for the Doctoral Program of Higher Education of China (20133402120033), the National Natural Science Foundation of China (81571768, 81627806), and the Natural Science Foundation of Anhui Province (1408085ME96). We would like to thank Research Center for Life Sciences at the University of Science and Technology of China for assistance.
Author Contributions
J.L. and W.D. developed the theoretical model. J.L. accomplished the numerical simulation and data analysis. R.R, W.D., M.C. and L.W. designed the experiments. R.R., L.Z., M.C. and P.W. conducted the experiments. J.L. wrote the manuscript with inputs from all co-authors. All authors reviewed the manuscript.
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The authors declare no competing financial interests.
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Associate Editor Aleksander S. Popel oversaw the review of this article.
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Liu, J., Ding, W., Ruan, R. et al. A Theoretical Study on Inhibition of Melanoma with Controlled and Targeted Delivery of siRNA via Skin Using SPACE-EGF. Ann Biomed Eng 45, 1407–1419 (2017). https://doi.org/10.1007/s10439-017-1825-5
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DOI: https://doi.org/10.1007/s10439-017-1825-5