Interpenetrating Polymer Network Hydrogels of Gelatin and Poly(ethylene glycol) as an Engineered 3D Tumor Microenvironment

Dong Shin Lee; Jeon Il Kang; Byeong Hee Hwang; Kyung Min Park

Macromolecular Research, Vol.27, No.2, 205-211, February, 2019

DOI10.1007/s13233-019-7072-x Export Citation

Interpenetrating Polymer Network Hydrogels of Gelatin and Poly(ethylene glycol) as an Engineered 3D Tumor Microenvironment

Dong Shin Lee¹, Jeon Il Kang¹, Byeong Hee Hwang^{2, 1, †}, and Kyung Min Park^{2, 1, †}

¹Department of Bioengineering and Nano-Bioengineering, Incheon National University, 119 Academy-ro, Yeonsu-gu, Incheon 22012, Korea
²Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, 119 Academy-ro, Yeonsu-gu, Incheon 22012, Korea

E-mail:,

An emerging trend in cancer research is to develop engineered tumor models using bio-inspired biomaterials that can mimic the native tumor microenvironment. Although various bio-inspired hydrogels have been utilized, it is still challenging to develop advanced polymeric hydrogel materials that can more accurately reconstruct critical aspects of the native tumor microenvironment. Herein, we present interpenetrating polymer network (IPN) hydrogels composed of thiolated gelatin and tyramine-conjugated poly(ethylene glycol), which form IPN hydrogels via horseradish peroxidase-mediated dual cross-linking reactions. We demonstrate that the IPN hydrogels exhibit independently controllable physicochemical properties. Also, the IPN hydrogels show resistance to the proteolytic enzymes and cytocompatibility for long-term culture of human fibrosarcoma (HT1080) cells. Moreover, we utilize the engineered tumor construct as a platform to evaluate the effect of matrix stiffness on cancer cell proliferation and drug resistance against the anticancer drug 5-fluorouracil as a model drug. In conclusion, we suggest that our IPN hydrogel is a promising material to study cancer biology and to screen innovative therapeutic agents for better clinical outcomes.

Keywords:polymeric hydrogels;injectable hydrogels;engineered tumor models;tumor microenvironments;drug resistance

[References]

Tessmer MS, Flaherty KT, Clin. Cancer Res., 23, 5325 (2017)
Davidson NE, Armstrong SA, Coussens LM, Cruz-Correa MR, et al., Clin. Cancer Res., 22 Suppl 19, S1 (2016).
Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J, Nat. Biotechnol., 32, 40 (2014)
De Palma M, Biziato D, Petrova TV, Nat. Rev. Cancer, 17, 457 (2017)
Quail DF, Joyce JA, Nat. Med., 19, 1423 (2013)
Kumar M, Dhatwalia SK, Dhawan DK, Tumour. Biol., 37, 14341 (2016)
Weis SM, Cheresh DA, Nat. Med., 17, 1359 (2011)
Ackerman D, Simon MC, Trends Cell Biol., 24, 472 (2014)
Park KM, Lewis D, Gerecht S, Annu. Rev. Biomed. Eng., 19, 109 (2017)
Park KM, Gerecht S, Eur. Polym. J., 72, 507 (2015)
Park S, Park KM, Biomaterials, 182, 234 (2018)
Park KM, Ko KS, Joung YK, Shin H, Park KD, J. Mater. Chem., 21, 13180 (2011)
Park KM, Blatchley MR, Gerecht S, Macromol. Rapid Commun., 35(22), 1968 (2014)
Park KM, Gerecht S, Nat. Commun., 5, 4075 (2014)
Park KM, Lee Y, Son JY, Oh DH, Lee JS, Park KD, Biomacromolecules, 13(3), 604 (2012)
Li C, Mu C, Lin W, Ngai T, ACS Appl. Mater. Interfaces, 7, 18732 (2015)
Kalia S, Polymeric Hydrogels as Smart Biomaterials, Springer, 2016.
Klotz BJ, Gawlitta D, Rosenberg A, Malda J, Melchels FPW, Trends Biotechnol., 34, 394 (2016)
Sokic S, Papavasiliou G, Tissue Eng. Part A, 18, 2477 (2012)
Raeber GP, Lutolf MP, Hubbell JA, Biophys. J., 89, 1374 (2005)
Zaton AM, Ochoa de Aspuru E, Febs Lett., 374, 192 (1995)
Safiri R, Sajedi RH, Jafarian V, J. Mol. Liq., 123, 20 (2006)
Edwards DR, Murphy G, Nature, 394, 527 (1998)
Coussens LM, Werb Z, Nature, 420, 860 (2002)
Kessenbrock K, Plaks V, Werb Z, Cell, 141, 52 (2010)
Shapiro SD, Curr. Opin. Cell Biol., 10, 602 (1998)
Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M, Nature, 370(6484), 61 (1994)
Kumar S, Weaver VM, Cancer Metastasis Rev., 28, 113 (2009)
Fukumura D, Jain RK, J. Cell. Biochem., 101, 937 (2007)
Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ, BMC Med., 6, 11 (2008)
Phelps EA, Enemchukwu NO, Fiore VF, Sy JC, Murthy N, Sulchek TA, Barker TH, Garcia AJ, Adv. Mater., 24(1), 64 (2012)
Starkov AA, Andreyev AY, Zhang SF, Starkova NN, Korneeva M, Syromyatnikov M, Popov VN, J. Bioenerg. Biomembr., 46, 471 (2014)
Slade L, Chalker J, Kuksal N, Young A, Gardiner D, Mailloux RJ, AAPG BullBiochim. Biophys. Acta Gen. Subj.., 1861, 1960 (2017)
Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E, Clin. Exp. Metastasis, 35, 309 (2018)
Rueff J, Rodrigues AS, Methods Mol. Biol., 1395, 1 (2016)
Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S, Cancers, 6, 1769 (2014)
Periti P, Mini E, J. Chemother., 1, 5 (1989)

[Referenced By]

[1] Tessmer MS, Flaherty KT, Clin. Cancer Res., 23, 5325 (2017)

[2] Davidson NE, Armstrong SA, Coussens LM, Cruz-Correa MR, et al., Clin. Cancer Res., 22 Suppl 19, S1 (2016).

[3] Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J, Nat. Biotechnol., 32, 40 (2014)

[4] De Palma M, Biziato D, Petrova TV, Nat. Rev. Cancer, 17, 457 (2017)

[5] Quail DF, Joyce JA, Nat. Med., 19, 1423 (2013)

[6] Kumar M, Dhatwalia SK, Dhawan DK, Tumour. Biol., 37, 14341 (2016)

[7] Weis SM, Cheresh DA, Nat. Med., 17, 1359 (2011)

[8] Ackerman D, Simon MC, Trends Cell Biol., 24, 472 (2014)

[9] Park KM, Lewis D, Gerecht S, Annu. Rev. Biomed. Eng., 19, 109 (2017)

[10] Park KM, Gerecht S, Eur. Polym. J., 72, 507 (2015)

[11] Park S, Park KM, Biomaterials, 182, 234 (2018)

[12] Park KM, Ko KS, Joung YK, Shin H, Park KD, J. Mater. Chem., 21, 13180 (2011)

[13] Park KM, Blatchley MR, Gerecht S, Macromol. Rapid Commun., 35(22), 1968 (2014)

[14] Park KM, Gerecht S, Nat. Commun., 5, 4075 (2014)

[15] Park KM, Lee Y, Son JY, Oh DH, Lee JS, Park KD, Biomacromolecules, 13(3), 604 (2012)

[16] Li C, Mu C, Lin W, Ngai T, ACS Appl. Mater. Interfaces, 7, 18732 (2015)

[17] Kalia S, Polymeric Hydrogels as Smart Biomaterials, Springer, 2016.

[18] Klotz BJ, Gawlitta D, Rosenberg A, Malda J, Melchels FPW, Trends Biotechnol., 34, 394 (2016)

[19] Sokic S, Papavasiliou G, Tissue Eng. Part A, 18, 2477 (2012)

[20] Raeber GP, Lutolf MP, Hubbell JA, Biophys. J., 89, 1374 (2005)

[21] Zaton AM, Ochoa de Aspuru E, Febs Lett., 374, 192 (1995)

[22] Safiri R, Sajedi RH, Jafarian V, J. Mol. Liq., 123, 20 (2006)

[23] Edwards DR, Murphy G, Nature, 394, 527 (1998)

[24] Coussens LM, Werb Z, Nature, 420, 860 (2002)

[25] Kessenbrock K, Plaks V, Werb Z, Cell, 141, 52 (2010)

[26] Shapiro SD, Curr. Opin. Cell Biol., 10, 602 (1998)

[27] Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M, Nature, 370(6484), 61 (1994)

[28] Kumar S, Weaver VM, Cancer Metastasis Rev., 28, 113 (2009)

[29] Fukumura D, Jain RK, J. Cell. Biochem., 101, 937 (2007)

[30] Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, White JG, Keely PJ, BMC Med., 6, 11 (2008)

[31] Phelps EA, Enemchukwu NO, Fiore VF, Sy JC, Murthy N, Sulchek TA, Barker TH, Garcia AJ, Adv. Mater., 24(1), 64 (2012)

[32] Starkov AA, Andreyev AY, Zhang SF, Starkova NN, Korneeva M, Syromyatnikov M, Popov VN, J. Bioenerg. Biomembr., 46, 471 (2014)

[33] Slade L, Chalker J, Kuksal N, Young A, Gardiner D, Mailloux RJ, AAPG BullBiochim. Biophys. Acta Gen. Subj.., 1861, 1960 (2017)

[34] Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E, Clin. Exp. Metastasis, 35, 309 (2018)

[35] Rueff J, Rodrigues AS, Methods Mol. Biol., 1395, 1 (2016)

[36] Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S, Cancers, 6, 1769 (2014)

[37] Periti P, Mini E, J. Chemother., 1, 5 (1989)