Skin Penetration-Inducing Gelatin Methacryloyl Nanogels for Transdermal Macromolecule Delivery

Jeehye Kim; Robert Gauvin; Hee Jeong Yoon; Jin-Hoi Kim; Sang-Mo Kwon; Hyun Jin Park; Sang Hong Baek; Jae Min Cha; Hojae Bae

Macromolecular Research, Vol.24, No.12, 1115-1125, December, 2016

DOI10.1007/s13233-016-4147-9 Export Citation

Skin Penetration-Inducing Gelatin Methacryloyl Nanogels for Transdermal Macromolecule Delivery

Jeehye Kim¹, Robert Gauvin², Hee Jeong Yoon¹, Jin-Hoi Kim³, Sang-Mo Kwon⁴, Hyun Jin Park⁵, Sang Hong Baek⁶, Jae Min Cha^{7, 8}, and Hojae Bae^{1, †}

¹College of Animal Bioscience and Technology, Department of Bioindustrial Technologies, Konkuk University, Hwayang-dong, Kwangjin-gu, Seoul 05029, Korea
²Quebec Center for Functional Materials (CQMF) and Department of Surgery, Faculty of Medicine, Université Laval, Quebec, Canada
³College of Animal Bioscience and Technology, Department of Stem Cell and Regenerative Biology, Konkuk University, Hwayang-dong, Kwangjin-gu, Seoul 05029, Korea
⁴Laboratory of Vascular Medicine & Stem Cell Biology, Department of Physiology, Pusan National University School of Medicine, Yangsan, Gyeongnam 50612, Korea
⁵School of Life Sciences and Biotechnology, Korea University, 5-ka, Anam-Dong, Sungbuk-Ku, Seoul 02841, Korea
⁶6Laboratory of Cardiovascular Regeneration, Division of Cardiology, Seoul St. Mary’s Hospital, The Catholic University of Korea School of Medicine, Seoul 02841, Korea
⁷Medical Device Research Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
⁸Samsung Biomedical Research Institute, Samsung Advanced Institute of Technology, Samsung Electronics Co., Ltd., Seoul 06620, Korea

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In this study, the suitability of gelatin methacryloyl (GelMA) nanogels for transdermal delivery of macromolecules was demonstrated. The synthesis of GelMA nanogels (GNs) and fluorescein isothiocyanate labelled bovine serum albumin (FITC-BSA) loaded GelMA nanogels (FGNs) were implemented when confined in waterin-oil nanoemulsion droplets via the photopolymerization of the methacryloyl substituents to create crosslinked nanogels. Both GNs and FGNs existed as fine particles in aqueous condition (pH 7.4) for 7 days. No distinct aggregation of nanogel particles were observed. In the MTT assay, high percentage of cell viability indicated that GNs did not exhibit any growth inhibitory effect or significant cytotoxicity. The skin penetration study results showed that FGNs permeated across the epidermis and into the dermis of a porcine model when compared to the FITC-BSA dissolved in PBS. Possible penetration routes of FITC-BSA through the stratum corneum (SC) were illustrated by visualizing the SC structure with fluorescent signals of FITC-BSA. The penetration mechanism of FGNs across the SC layer was successfully demonstrated by explaining three penetration routes (intercellular, follicular, and transcellular route). The results suggest that GNs have a potential as a transdermal delivery carrier for hydrophilic macromolecules.

Keywords:nanogels;transdermal delivery;intracellular protein delivery;photocrosslinkable polymers;biodegradable polymers;polymeric carrier

[References]

Farokhzad OC, Langer R, ACS Nano, 3, 16 (2009)
Shi J, Votruba AR, Farokhzad OC, Langer R, Nano Lett., 10, 3223 (2010)
Yallapu MM, Jaggi M, Chauhan SC, Drug Discov. Today, 16, 457 (2011)
Yallapu MM, Reddy MK, Labhasetwar V, in Biomedical Appl. Nanotechnol., John Wiley & Sons, Inc., New Jersey, 2007, p 131.
Kakadia PG, Conway BR, Am. J. Pharmacol. Sci., 2, 1 (2014)
Zhang S, Ermann J, Succi MD, Zhou A, Hamilton MJ, Cao B, Korzenik JR, Glickman JN, Vemula PK, Glimcher LH, Traverso G, Langer R, Karp JM, Sci. Transl. Med., 7, 300ra1 (2015)
Hoare TR, Kohane DS, Polymer, 49(8), 1993 (2008)
Hoffman AS, Adv. Drug Deliv. Rev., 64, 18 (2012)
Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A, Peppas NA, Adv. Mater., 21(32-33), 3307 (2009)
Groll J, Singh S, Albrecht K, Moeller M, J. Polym. Sci. A: Polym. Chem., 47(20), 5543 (2009)
Ogawa K, Nakayama A, Kokufuta E, Langmuir, 19(8), 3178 (2003)
Vincent B, in Surface Chemistry in Biomedical and Environmental Science, Springer, Dordrecht, 2006, pp 11-22.
Vinogradov SV, Bronich TK, Kabanov AV, Adv. Drug Deliv. Rev., 54, 135 (2002)
Ammala A, Int. J. Cosmet. Sci., 35, 113 (2013)
Nair LS, Laurencin CT, Prog. Polym. Sci, 32, 762 (2007)
Prausnitz MR, Langer R, Nat. Biotechnol., 26, 1261 (2008)
Kong M, Park H, Feng C, Hou L, Cheng X, Chen X, Carbohydr. Polym., 94, 634 (2013)
Godwin DA, Kim NH, Felton LA, Eur. J. Pharm. Biopharm., 53, 23 (2002)
Prausnitz MR, Mitragotri S, Langer R, Nat. Rev. Drug Discov., 3, 115 (2004)
Lee KY, Mooney DJ, Prog. Polym. Sci, 37, 106 (2012)
Knipe JM, Strong LE, Peppas NA, Biomacromolecules, 17(3), 788 (2016)
Polat BE, Blankschtein D, Langer R, Expert Opin. Drug Deliv., 7, 1415 (2010)
Subongkot T, Wonglertnirant N, Songprakhon P, Rojanarata T, Opanasopit P, Ngawhirunpat T, Int. J. Pharm., 441, 151 (2013)
Nichol JW, Koshy ST, Bae H, Hwang CM, Yamanlar S, Khademhosseini A, Biomaterials, 31, 5536 (2010)
Yue K, Trujillo-de Santiago G, Alvarez MM, Tamayol A, Annabi N, Khademhosseini A, Biomaterials, 73, 254 (2015)
Van den Bulcke AI, Bogdanov B, De Rooze N, Schacht EH, Cornelissen M, Berghmans H, Biomacromolecules, 1(1), 31 (2000)
Hiemenz PC, Principles of Colloid and Surface Chemistry, Marcel Dekker, New York, 1986.
Bingaman S, Huxley VH, Rumbaut RE, Microcirculation, 10, 221 (2003)
Malkinson FD, J. Invest. Dermatol., 31, 19 (1958)
Monash S, J. Invest. Dermatol., 29, 367 (1957)
Forster M, Bolzinger MA, Fessi H, Briancon S, Eur. J. Dermatol., 19, 309 (2009)
Lauterbach A, Muller-Goymann CC, Eur. J. Pharm. Biopharm., 97, 152 (2015)
Escobar-Chavez JJ, Skin, 19, 22 (2012)
Volz P, Boreham A, Wolf A, Kim TY, Balke J, Frombach J, Hadam S, Afraz Z, Rancan F, Blume-Peytavi U, Vogt A, Alexiev U, Int. J. Mol. Sci., 16(4), 6960 (2015)
Cevc G, Vierl U, J. Control. Release, 141, 277 (2010)
Cui H, Quan P, Zhao H, Wen X, Song W, Xiao Y, Zhao Y, Fang L, J. Pharm. Sci., 104, 3395 (2015)
Garidel P, Phys. Chem. Chem. Phys., 4, 5671 (2002)
Hadgraft J, Lane ME, Phys. Chem. Chem. Phys., 13, 5215 (2011)
Alkilani A, McCrudden MT, Donnelly R, Pharmaceutics, 7, 438 (2015)
Nair LS, Laurencin CT, Prog. Polym. Sci, 32, 762 (2007)

[1] Farokhzad OC, Langer R, ACS Nano, 3, 16 (2009)

[2] Shi J, Votruba AR, Farokhzad OC, Langer R, Nano Lett., 10, 3223 (2010)

[3] Yallapu MM, Jaggi M, Chauhan SC, Drug Discov. Today, 16, 457 (2011)

[4] Yallapu MM, Reddy MK, Labhasetwar V, in Biomedical Appl. Nanotechnol., John Wiley & Sons, Inc., New Jersey, 2007, p 131.

[5] Kakadia PG, Conway BR, Am. J. Pharmacol. Sci., 2, 1 (2014)

[6] Zhang S, Ermann J, Succi MD, Zhou A, Hamilton MJ, Cao B, Korzenik JR, Glickman JN, Vemula PK, Glimcher LH, Traverso G, Langer R, Karp JM, Sci. Transl. Med., 7, 300ra1 (2015)

[7] Hoare TR, Kohane DS, Polymer, 49(8), 1993 (2008)

[8] Hoffman AS, Adv. Drug Deliv. Rev., 64, 18 (2012)

[9] Slaughter BV, Khurshid SS, Fisher OZ, Khademhosseini A, Peppas NA, Adv. Mater., 21(32-33), 3307 (2009)

[10] Groll J, Singh S, Albrecht K, Moeller M, J. Polym. Sci. A: Polym. Chem., 47(20), 5543 (2009)

[11] Ogawa K, Nakayama A, Kokufuta E, Langmuir, 19(8), 3178 (2003)

[12] Vincent B, in Surface Chemistry in Biomedical and Environmental Science, Springer, Dordrecht, 2006, pp 11-22.

[13] Vinogradov SV, Bronich TK, Kabanov AV, Adv. Drug Deliv. Rev., 54, 135 (2002)

[14] Ammala A, Int. J. Cosmet. Sci., 35, 113 (2013)

[15] Nair LS, Laurencin CT, Prog. Polym. Sci, 32, 762 (2007)

[16] Prausnitz MR, Langer R, Nat. Biotechnol., 26, 1261 (2008)

[17] Kong M, Park H, Feng C, Hou L, Cheng X, Chen X, Carbohydr. Polym., 94, 634 (2013)

[18] Godwin DA, Kim NH, Felton LA, Eur. J. Pharm. Biopharm., 53, 23 (2002)

[19] Prausnitz MR, Mitragotri S, Langer R, Nat. Rev. Drug Discov., 3, 115 (2004)

[20] Lee KY, Mooney DJ, Prog. Polym. Sci, 37, 106 (2012)

[21] Knipe JM, Strong LE, Peppas NA, Biomacromolecules, 17(3), 788 (2016)

[22] Polat BE, Blankschtein D, Langer R, Expert Opin. Drug Deliv., 7, 1415 (2010)

[23] Subongkot T, Wonglertnirant N, Songprakhon P, Rojanarata T, Opanasopit P, Ngawhirunpat T, Int. J. Pharm., 441, 151 (2013)

[24] Nichol JW, Koshy ST, Bae H, Hwang CM, Yamanlar S, Khademhosseini A, Biomaterials, 31, 5536 (2010)

[25] Yue K, Trujillo-de Santiago G, Alvarez MM, Tamayol A, Annabi N, Khademhosseini A, Biomaterials, 73, 254 (2015)

[26] Van den Bulcke AI, Bogdanov B, De Rooze N, Schacht EH, Cornelissen M, Berghmans H, Biomacromolecules, 1(1), 31 (2000)

[27] Hiemenz PC, Principles of Colloid and Surface Chemistry, Marcel Dekker, New York, 1986.

[28] Bingaman S, Huxley VH, Rumbaut RE, Microcirculation, 10, 221 (2003)

[29] Malkinson FD, J. Invest. Dermatol., 31, 19 (1958)

[30] Monash S, J. Invest. Dermatol., 29, 367 (1957)

[31] Forster M, Bolzinger MA, Fessi H, Briancon S, Eur. J. Dermatol., 19, 309 (2009)

[32] Lauterbach A, Muller-Goymann CC, Eur. J. Pharm. Biopharm., 97, 152 (2015)

[33] Escobar-Chavez JJ, Skin, 19, 22 (2012)

[34] Volz P, Boreham A, Wolf A, Kim TY, Balke J, Frombach J, Hadam S, Afraz Z, Rancan F, Blume-Peytavi U, Vogt A, Alexiev U, Int. J. Mol. Sci., 16(4), 6960 (2015)

[35] Cevc G, Vierl U, J. Control. Release, 141, 277 (2010)

[36] Cui H, Quan P, Zhao H, Wen X, Song W, Xiao Y, Zhao Y, Fang L, J. Pharm. Sci., 104, 3395 (2015)

[37] Garidel P, Phys. Chem. Chem. Phys., 4, 5671 (2002)

[38] Hadgraft J, Lane ME, Phys. Chem. Chem. Phys., 13, 5215 (2011)

[39] Alkilani A, McCrudden MT, Donnelly R, Pharmaceutics, 7, 438 (2015)

[40] Nair LS, Laurencin CT, Prog. Polym. Sci, 32, 762 (2007)