pH-Responsive mineralized nanoparticles for bacteria-triggered topical release of antibiotics

Kyung Hyun Min; Eun-Young Jang; Hong Jae Lee; Yu-Shik Hwang; Jae-In Ryu; Ji-Hoi Moon; Sang Cheon Lee

Journal of Industrial and Engineering Chemistry, Vol.71, 210-219, March, 2019

DOI10.1016/j.jiec.2018.11.027 Export Citation

pH-Responsive mineralized nanoparticles for bacteria-triggered topical release of antibiotics

Kyung Hyun Min¹, Eun-Young Jang², Hong Jae Lee¹, Yu-Shik Hwang¹, Jae-In Ryu³, Ji-Hoi Moon^{1, 4, †}, and Sang Cheon Lee^{1, †}

¹Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
²Department of Dentistry, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
³Department of Preventive and Social Dentistry, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea
⁴Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 02447, Republic of Korea

E-mail:,

We report on doxycycline (DOXY)-loaded calcium carbonate (CaCO3) mineralized nanoparticles (DOXY- MNPs) that can induce selective topical release of antibiotics to target oral plaque biofilms with acidic pH (ca. 4.5-5.5). The DOXY-MNPs were fabricated through a block copolymer-templated mineralization approach with simultaneous loading of an antibacterial drug, DOXY. The CaCO3 mineral core of DOXY- MNPs inhibited the leakage of entrapped DOXY in environments with normal salivary pH. However, in acidic pH, the DOXY release was triggered by the dissolution of CaCO3 mineral cores. The DOXY-MNPs showed effective antibacterial therapeutic activity to Prevotella intermedia bacterial cells with a potent treatment of biofilms.

Keywords:pH-responsive;Bacteria-triggered;Topical delivery;Calcium carbonate;Doxycycline

[References]

Parsek MR, Fuqua C, J. Bacteriol., 186, 4427 (2004)
Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg E, Nature, 407, 762 (2000)
Jin L, Armitage G, Klinge B, Lang N, Tonetti M, Williams R, Adv. Dental Res., 23, 221 (2011)
Beikler T, Flemmig TF, Periodontol 2000 55, 87 (2011).
Burgers R, Gerlach T, Hahnel S, Schwarz F, Handel G, Gosau M, Clin. Oral Implants Res., 21, 156 (2010)
Koo H, Falsetta M, Klein M, J. Dent. Res., 92, 1065 (2013)
Takahashi N, Nyvad B, J. Dent. Res., 90, 294 (2011)
Carcuac O, Derks J, Charalampakis G, Abrahamsson I, Wennstrom J, Berglundh T, J. Dent. Res., 95, 50 (2016)
Hall-Stoodley L, Costerton JW, Stoodley P, Nat. Rev. Microbio., 2, 95 (2004)
Costerton JW, Stewart PS, Greenberg EP, Science, 284(5418), 1318 (1999)
Flemming HC, Wingender J, Nat. Rev. Microbio., 8, 623 (2010)
Rams TE, Keyes PH, J. Am. Dent. Assoc., 1939, 37 (1983)
Prakasam A, Elavarasu S, Natarajan RK, J. Pharm. Bioallied Sci., 4(Suppl 2), S252 (2012)
Kapoor A, Malhotra R, Grover V, Grover D, Dent. Res. J., 9, 505 (2012)
Xiao J, Klein MI, Falsetta ML, Lu B, Delahunty CM, Yates JR III, Heydorn A, Koo H, PLoS Path., 8, e10026 (2012)
Stewart PS, Int. J. Med. Microbiol., 292, 107 (2002)
Høiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O, Int. J. Antimicrob. Agents, 35, 322 (2010)
Zhuk I, Jariwala F, Attygalle AB, Wu Y, Libera MR, Sukhishvili SA, ACS Nano, 8, 7733 (2014)
Horev B, Klein MI, Hwang G, Li Y, Kim D, Koo H, Benoit DSW, ACS Nano, 9, 2390 (2015)
Lee HS, Dastgheyb SS, Hickok NJ, Eckmann DM, Composto RJ, Biomacromolecules, 16(2), 650 (2015)
Min KH, Min HS, Lee HJ, Park DJ, Yhee JY, Kim K, Kwon IC, Jeong SY, Silvestre OF, Chen X, ACS Nano, 9, 134 (2015)
Park DJ, Min KH, Lee HJ, Kim K, Kwon IC, Jeong SY, Lee SC, J. Mater. Chem. B, 4(7), 1219 (2016)
Min KH, Lee HJ, Kim K, Kwon IC, Jeong SY, Lee SC, Biomaterials, 33, 5788 (2012)
Koo AN, Min KH, Lee HJ, Jegal JH, Lee JW, Lee SC, Chem. Asian J., 10, 2380 (2015)
Yang Q, Wang S, Fan P, Wang L, Di Y, Lin K, Xiao FS, Chem. Mater., 17, 5999 (2005)
Ogomi D, Serizawa T, Akashi M, J. Control. Release, 103, 315 (2005)
Choi B, Park H, Hwang S, Park J, Int. J. Pharm., 239, 81 (2002)
Weiner S, Addadi L, J. Mater. Chem., 7, 689 (1997)
Phadke A, Zhang C, Hwang Y, Vecchio K, Varghese S, Biomacromolecules, 11(8), 2060 (2010)
Li Y, Burne RA, Microbiology, 147, 2841 (2001)
Lee HJ, Kim DE, Park DJ, Choi GH, Yang DN, Heo JS, Lee SC, Colloids Surf. B: Biointerfaces, 146, 1 (2016)
Jegal JH, Choi GH, Lee HJ, Kim KD, Lee SC, Macromol. Res., 24(1), 83 (2016)
Singh SVB, Kim JH, Park HY, Khang GS, Lee DW, Macromol. Res., 25(7), 749 (2017)
Kim S, Kwag DS, Lee DJ, Lee ES, Macromol. Res., 24(2), 176 (2016)
Yadav SK, Mishra B, J. Chem. Pharm. Res., 8, 564 (2016)
Ashimoto A, Chen C, Bakker I, Slots J, Mol. Oral Microbiol., 11, 266 (1996)
Albandar JM, Brown LJ, Loe HJ, Periodontology, 68, 973 (1997)
Rowland RW, Mestecky J, Gunsolley JC, Cogen RB, J. Periodontol., 64, 195 (1993)
Gomes B, Drucker D, Lilley J, Int. Endod. J., 27, 291 (1994)
Bolivar I, Whiteson K, Stadelmann B, Baratti-Mayer D, Gizard Y, Mombelli A, Pittet D, Schrenzel J, PLoS Negl. Trop. Dis., 6, e1556 (2012)
Ulrich M, Beer I, Braitmaier P, Dierkes M, Kummer F, Krismer B, Schumacher U, Grapler-Mainka U, Riethmuller J, Jensen PO, Thorax, 65, 978 (2010)
Fiehn NE, Larsen T, Christiansen N, Holmstrup P, Schroeder TV, J. Periodontol., 76, 731 (2005)
Takahashi N, Yamada T, Mol. Oral Microbiol., 15, 188 (2000)
Moon JH, Jang EY, Shim KS, Lee JY, J. Microbiol., 53, 321 (2015)
Takahash K, Ishihara R, Kimizuka K, Okuda T, Kato M, Oral Microbiol., 21, 366 (2006)

[1] Parsek MR, Fuqua C, J. Bacteriol., 186, 4427 (2004)

[2] Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ, Greenberg E, Nature, 407, 762 (2000)

[3] Jin L, Armitage G, Klinge B, Lang N, Tonetti M, Williams R, Adv. Dental Res., 23, 221 (2011)

[4] Beikler T, Flemmig TF, Periodontol 2000 55, 87 (2011).

[5] Burgers R, Gerlach T, Hahnel S, Schwarz F, Handel G, Gosau M, Clin. Oral Implants Res., 21, 156 (2010)

[6] Koo H, Falsetta M, Klein M, J. Dent. Res., 92, 1065 (2013)

[7] Takahashi N, Nyvad B, J. Dent. Res., 90, 294 (2011)

[8] Carcuac O, Derks J, Charalampakis G, Abrahamsson I, Wennstrom J, Berglundh T, J. Dent. Res., 95, 50 (2016)

[9] Hall-Stoodley L, Costerton JW, Stoodley P, Nat. Rev. Microbio., 2, 95 (2004)

[10] Costerton JW, Stewart PS, Greenberg EP, Science, 284(5418), 1318 (1999)

[11] Flemming HC, Wingender J, Nat. Rev. Microbio., 8, 623 (2010)

[12] Rams TE, Keyes PH, J. Am. Dent. Assoc., 1939, 37 (1983)

[13] Prakasam A, Elavarasu S, Natarajan RK, J. Pharm. Bioallied Sci., 4(Suppl 2), S252 (2012)

[14] Kapoor A, Malhotra R, Grover V, Grover D, Dent. Res. J., 9, 505 (2012)

[15] Xiao J, Klein MI, Falsetta ML, Lu B, Delahunty CM, Yates JR III, Heydorn A, Koo H, PLoS Path., 8, e10026 (2012)

[16] Stewart PS, Int. J. Med. Microbiol., 292, 107 (2002)

[17] Høiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O, Int. J. Antimicrob. Agents, 35, 322 (2010)

[18] Zhuk I, Jariwala F, Attygalle AB, Wu Y, Libera MR, Sukhishvili SA, ACS Nano, 8, 7733 (2014)

[19] Horev B, Klein MI, Hwang G, Li Y, Kim D, Koo H, Benoit DSW, ACS Nano, 9, 2390 (2015)

[20] Lee HS, Dastgheyb SS, Hickok NJ, Eckmann DM, Composto RJ, Biomacromolecules, 16(2), 650 (2015)

[21] Min KH, Min HS, Lee HJ, Park DJ, Yhee JY, Kim K, Kwon IC, Jeong SY, Silvestre OF, Chen X, ACS Nano, 9, 134 (2015)

[22] Park DJ, Min KH, Lee HJ, Kim K, Kwon IC, Jeong SY, Lee SC, J. Mater. Chem. B, 4(7), 1219 (2016)

[23] Min KH, Lee HJ, Kim K, Kwon IC, Jeong SY, Lee SC, Biomaterials, 33, 5788 (2012)

[24] Koo AN, Min KH, Lee HJ, Jegal JH, Lee JW, Lee SC, Chem. Asian J., 10, 2380 (2015)

[25] Yang Q, Wang S, Fan P, Wang L, Di Y, Lin K, Xiao FS, Chem. Mater., 17, 5999 (2005)

[26] Ogomi D, Serizawa T, Akashi M, J. Control. Release, 103, 315 (2005)

[27] Choi B, Park H, Hwang S, Park J, Int. J. Pharm., 239, 81 (2002)

[28] Weiner S, Addadi L, J. Mater. Chem., 7, 689 (1997)

[29] Phadke A, Zhang C, Hwang Y, Vecchio K, Varghese S, Biomacromolecules, 11(8), 2060 (2010)

[30] Li Y, Burne RA, Microbiology, 147, 2841 (2001)

[31] Lee HJ, Kim DE, Park DJ, Choi GH, Yang DN, Heo JS, Lee SC, Colloids Surf. B: Biointerfaces, 146, 1 (2016)

[32] Jegal JH, Choi GH, Lee HJ, Kim KD, Lee SC, Macromol. Res., 24(1), 83 (2016)

[33] Singh SVB, Kim JH, Park HY, Khang GS, Lee DW, Macromol. Res., 25(7), 749 (2017)

[34] Kim S, Kwag DS, Lee DJ, Lee ES, Macromol. Res., 24(2), 176 (2016)

[35] Yadav SK, Mishra B, J. Chem. Pharm. Res., 8, 564 (2016)

[36] Ashimoto A, Chen C, Bakker I, Slots J, Mol. Oral Microbiol., 11, 266 (1996)

[37] Albandar JM, Brown LJ, Loe HJ, Periodontology, 68, 973 (1997)

[38] Rowland RW, Mestecky J, Gunsolley JC, Cogen RB, J. Periodontol., 64, 195 (1993)

[39] Gomes B, Drucker D, Lilley J, Int. Endod. J., 27, 291 (1994)

[40] Bolivar I, Whiteson K, Stadelmann B, Baratti-Mayer D, Gizard Y, Mombelli A, Pittet D, Schrenzel J, PLoS Negl. Trop. Dis., 6, e1556 (2012)

[41] Ulrich M, Beer I, Braitmaier P, Dierkes M, Kummer F, Krismer B, Schumacher U, Grapler-Mainka U, Riethmuller J, Jensen PO, Thorax, 65, 978 (2010)

[42] Fiehn NE, Larsen T, Christiansen N, Holmstrup P, Schroeder TV, J. Periodontol., 76, 731 (2005)

[43] Takahashi N, Yamada T, Mol. Oral Microbiol., 15, 188 (2000)

[44] Moon JH, Jang EY, Shim KS, Lee JY, J. Microbiol., 53, 321 (2015)

[45] Takahash K, Ishihara R, Kimizuka K, Okuda T, Kato M, Oral Microbiol., 21, 366 (2006)