Journal of Industrial and Engineering Chemistry, Vol.104, 93-105, December, 2021
In vitro study of doxorubicin-loaded thermo- and pH-tunable carriers for targeted drug delivery to liver cancer cells
E-mail:,
In this study, a series of thermo- and pH-dependent doxorubicin (DOX) carriers based on magnetic graphene nanosheets (MGNSs), functionalized by poly(N-isopropylacrylamide) (PNIPAM) and polyethylenemine (PEI) nanogel, targeting liver cancer cells were formulated. The temperature phase transitions of the carriers can be tuned as a function of pH to the intended value in the range of 38-42 °C. In vitro studies showed a high cell viability of above 90% at all doses of MGNSs and MGNS-nanogel against HEK293T normal and HepG2 cancerous cells, confirming the biocompatibility and nontoxicity of the carriers. In comparison, the MGNS-nanogel-DOX demonstrated a sufficient therapeutic effect towards HepG2 cell line. The cell viability results showed enhanced efficacy of the drug released by means of applied magnetic field (AMF). Moreover, an efficient cellular intake of the carriers into the HepG2 cells was achieved. Additionally, the achieved low DOX release at a lower temperature and neutral pH can retain the drug in the carriers until reaching the targeted sites. Nevertheless, the high drug release showed that the release was triggered by high temperature and acidic pH. Hence, the developed thermo- and pHtunable MGNS-nanogel-DOX showed a high potential for microenvironment stimulus-prompted drug delivery and cancer cell suppression.
Keywords:Magnetic graphene nanosheet;Stimulus-dependent;Thermo- and pH-dependent carrier;Doxorubicin;Nanogel
- Goodarzi E, Ghorat F, Jarrahi AM, Adineh HA, Sohrabivafa M, Khazaei Z, World Cancer Res. J., 6, 12 (2019)
- Sedighi M, Rahimi F, Shahbazi MA, Rezayan AH, Kettiger H, Einfalt T, Huwyler J, Witzigmann D, ACS Appl. Bio. Mater., 3, 239 (2019)
- Dehvari K, Lin KS, Wang SSS, Int. J. Nanosci. Nanotechnol., 14, 361 (2014)
- Dani RK, Schumann C, Taratula O, Taratula O, AAPS PharmSciTech., 15, 963 (2014)
- Zhang A, Jung K, Li A, Liu J, Boyer C, Prog. Polym. Sci., 99 (2019)
- Mdlovu NV, Lin KS, Weng MT, Hsieh CC, Lin YS, Espinoza MJC, J. Ind. Eng. Chem, Doi: 10.1016/j.jiec.2021.06.004.
- Mura S, Nicolas J, Couvreur P, Nat. Mater., 12(11), 991 (2013)
- Lopes JR, Santos G, Barata P, Oliveira R, Lopes CM, Curr. Pharm. Des., 19, 7169 (2013)
- Chen YS, Yoon SJ, Frey W, Dockery M, Emelianov S, Nat. Commun., 8, 1 (2017)
- Das SS, Bharadwaj P, Bilal M, Barani M, Rahdar A, Taboada P, Bungau S, Kyzas GZ, Polymers, 12, 1397 (2020)
- Eskandari Z, Abousalman-Rezvani S, Hajebi H, Roghani-Mamaqani M, Eur. Polym. J., 135 (2020)
- Cheng R, Meng F, Deng C, Klok HA, Zhong Z, Biomaterials, 34, 3647 (2013)
- Zhang W, Uthaman S, Song W, Eom KH, Jeon SH, Huh KM, Babu A, Park IK, Kim I, ACS Biomater. Sci. Eng., 6, 5012 (2020)
- Cheng R, Meng F, Deng C, Klok HA, Zhong Z, Biomaterials, 34, 3647 (2013)
- Eskandari P, Abousalman-Rezvani Z, Hajebi S, Roghani-Mamaqani H, Salami-Kalajahi M, Eur. Polym. J., 135 (2020)
- Buller J, Laschewsky A, Lutz JF, Wischerhoff E, Polym. Chem., 2, 1486 (2011)
- Karimi M, et al., ACS Appl Mater. Interfaces, 8, 21107 (2016)
- Okudan A, Altay A, Int. J. Polym. Sci., 2019 (2019)
- Wong JE, Gaharwar AK, Muller-Schulte D, Bahadur D, Richtering W, J. Colloid Interface Sci., 324(1-2), 47 (2008)
- Yam CH, Lee CH, Siu YS, Ho KM, Li P, Polymer, 106, 294 (2016)
- Lang XL, Lenart WR, Sun JEP, Hammouda B, Hore MJA, Macromolecules, 50(5), 2145 (2017)
- Deka SR, Quarta A, Di Corato R, Riedinger A, Cingolani R, Pellegrino T, Nanoscale, 3, 619 (2011)
- Still T, Chen K, Alsayed AM, Aptowicz KB, Yodh AG, J. Colloid Interface Sci., 405, 96 (2013)
- Kang EB, Sharker SM, In I, Park SY, J. Ind. Eng. Chem., 43, 150 (2016)
- Nogueira DR, Tavano L, Mitjans M, Perez L, Infante MR, Vinardell MP, Biomaterials, 34, 2758 (2013)
- Pourjavadi A, Tehrani ZM, Jokar S, J. Ind. Eng. Chem., 28, 45 (2015)
- Chen CY, Kim TH, Wu WC, Huang CM, Wei H, Mount CW, Tian Y, Jang SH, Pun SH, Jen AKY, Biomaterials, 34, 4501 (2013)
- Espinoza MJC, Lin KS, Weng MT, Kunene SC, Wang SSS, Eur. Polym. J., 153 (2021)
- Zhao X, Zou X, Ye L, J. Ind. Eng. Chem., 49, 36 (2017)
- Heo JW, Tanum J, Park SY, Choi DE, Jeong HJ, Han UY, Hong JK, J. Ind. Eng. Chem., 88, 312 (2020)
- Justin R, Chen B, Interface Focus, 8, 201700 (2018)
- Pham TT, Nguyen HT, Phung CD, Pathak S, Regmi S, Ha DH, Kim JO, Yong CS, Kim SK, Choi JE, Yook SY, Park JB, Jeong JH, J. Ind. Eng. Chem., 76, 310 (2019)
- Latorre A, Couleaud P, Aires A, Cortajarena AL, Somoza A, Eur. J. Med. Chem., 82, 355 (2014)
- Hervault A, Dunn AE, Lim M, Boyer C, Mott D, Maenosono S, Thanh NT, Nanoscale, 8, 12152 (2016)
- Mdlovu NV, Mavuso FA, Lin KS, Chang TW, Chen Y, Wang SSS, Wu CM, Mdlovu NB, Lin YS, Colloids Surf. A: Physicochem. Eng. Asp., 562, 361 (2019)
- Bae KH, Park M, Do MJ, Lee N, Ryu JH, Kim GW, et al., ACS Nano, 26, 5266 (2012)
- Yang X, Zhang X, Ma Y, Huang Y, Wang Y, Chen Y, J. Mater. Chem., 19, 2710 (2009)
- Ma X, Tao H, Yang K, Feng L, Cheng L, Shi X, Li Y, Guo L, Liu Z, Nano Res., 5, 199 (2012)
- Shi X, Gong H, Li Y, Wang C, Cheng L, Liu Z, Biomaterials, 34, 4786 (2013)
- Ren LL, Huang S, Fan W, Liu TX, Appl. Surf. Sci., 258(3), 1132 (2011)
- Yang K, Hu LL, Ma XX, Ye SQ, Cheng L, Shi XZ, Li CH, Li YG, Liu Z, Adv. Mater., 24(14), 1868 (2012)
- Robinson JT, Tabakman SM, Liang YY, Wang HL, Casalongue HS, Vinh D, Dai HJ, J. Am. Chem. Soc., 133(17), 6825 (2011)
- Lin LS, Cong ZX, Cao JB, Ke KM, Peng QL, Gao J, Yang HH, Liu G, Chen X, ACS Nano, 8, 3876 (2014)
- Nayeem J, Al-Bari MAA, Mahiuddin M, Rahman MA, Mefford OT, Ahmad H, Rahman MM, Colloids Surf. A: Physicochem. Eng. Asp., 611 (2021)
- Pruettiphap M, Rempel GL, Pan Q, Kiatkamjornwong S, Iran. Polym. J., 26, 957 (2017)
- Sanzari I, Buratti E, Huang R, Tusan CG, Dinelli F, Evans ND, Prodromakis T, Bertoldo M, Sci. Rep., 10, 1 (2020)
- Vihola H, Laukkanen A, Valtola L, Tenhu H, Hirvonen J, Biomaterials, 26, 3055 (2005)
- Zintchenko A, Ogris M, Wagner E, Bioconjug. Chem., 17, 766 (2006)
- Singh A, Vaishagya K, Verma RK, Shukla R, AAPS PharmSciTech., 20, 1 (2019)
- Cai J, Chen G, Jin R, Deng C, Huang S, Yuan X, Chen G, Zhao J, Wang Z, Ai H, J. Ind. Eng. Chem., 76, 188 (2019)
- Bardajee GR, Hooshyar Z, Polym. Bull., 75(12), 5403 (2018)
- Justin R, Tao K, Roman S, Chen D, Xu Y, Geng X, Ross IM, Grant RT, Pearson A, Zhou G, MacNeil S, Carbon, 97, 54 (2016)
- Dubey NC, Tripathi BP, Muller M, Stamm M, Ionov L, ACS Appl. Mater. Interfaces, 7, 1500 (2015)
- Mdlovu NV, Lin KS, Chen Y, Wu CM, Colloids Surf. A: Physicochem. Eng. Asp., 126264 (2021)
- Mdlovu NV, Chen Y, Lin KS, Hsu MW, Wang SSS, Wu CM, Lin YS, Ohishi K, J. Taiwan Inst. Chem. Eng., 96, 526 (2019)
- Dehvari K, Chen Y, Tsai YH, Tseng SH, Lin KS, J. Biomed. Nanotechnol., 12, 1734 (2016)
- Kim YK, Kim EJ, Lim JH, Cho HK, Hong WJ, Jeon HH, Chung BG, Nanoscale Res. Lett., 14, 1 (2019)