Research Article

Metronidazole-loaded polydopamine nanomedicine with antioxidant and antibacterial bioactivity for periodontitis

Key Laboratory for Biorheological Science & Technology of Ministry of Education, State & Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400044, China

‡Authors contributed equally

Search for more papers by this author

Wen Liang‡

Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, China

‡Authors contributed equally

Search for more papers by this author

Lan Du

Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, China

Search for more papers by this author

Rongjuan Guo

Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, China

Search for more papers by this author

Yu Cao

Search for more papers by this author

Sheng Ni

Search for more papers by this author

Yuan Zhong

Search for more papers by this author

Kun Zhang

Chongqing University Three Gorges Hospital, Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, 404000, China

Search for more papers by this author

Kai Qu

Chongqing University Three Gorges Hospital, Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, 404000, China

Search for more papers by this author

Xian Qin

Chongqing University Three Gorges Hospital, Chongqing Municipality Clinical Research Center for Geriatric Diseases, Chongqing, 404000, China

Search for more papers by this author

Liang Chen

*Author for correspondence:

E-mail Address: chenliang@hospital.cqmu.edu.cn

https://orcid.org/0000-0003-0273-1387

Stomatological Hospital of Chongqing Medical University, Chongqing, 401147, China

Search for more papers by this author

Wei Wu

**Author for correspondence:

E-mail Address: david2015@cqu.edu.cn

https://orcid.org/0000-0003-3900-5135

Search for more papers by this author

Published Online:21 Dec 2023https://doi.org/10.2217/nnm-2023-0245

View article

Abstract

Aim: This study focused on treating periodontitis with bacterial infection and local over accumulation of reactive oxygen species. Materials & methods: Polydopamine nanoparticles (PDA NPs) were exploited as efficient carriers for encapsulated metronidazole (MNZ). The therapeutic efficacy and biocompatibility of PDA@MNZ NPs were investigated through both in vitro and in vivo studies. Results: The nanodrug PDA@MNZ NPs were successfully fabricated, with well-defined physicochemical characteristics. In vitro, the PDA@MNZ NPs effectively eliminated intracellular reactive oxygen species and inhibited the growth of Porphyromonas gingivalis. Moreover, the PDA@MNZ NPs exhibited synergistic therapy for periodontitisin in vivo. Conclusion: PDA@MNZ NPs were confirmed with exceptional antimicrobial and antioxidant functions, offering a promising avenue for synergistic therapy in periodontitis.

Tweetable abstract

A nanotherapeutic composed of dopamine nanoparticles loaded with metronidazole exhibited antimicrobial and antioxidative activities, presenting a safe and effective approach to periodontitis.

Keywords:

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

1. Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat. Rev. Dis. Primers 3, 17038 (2017). • Review of periodontal diseases.
MedlineGoogle Scholar
2. Peres MA, Macpherson LMD, Weyant RJ et al. Oral diseases: a global public health challenge. Lancet 394(10194), 249–260 (2019).
MedlineGoogle Scholar
3. Global Oral Health Status Report: Towards Universal Health Coverage for Oral Health by 2030. Geneva: World Health Organization (2022). Licence: CC BY-NC-SA 3.0 IGO.
Google Scholar
4. Frencken JE, Sharma P, Stenhouse L, Green D, Laverty D, Dietrich T. Global epidemiology of dental caries and severe periodontitis – a comprehensive review. J. Clin. Periodontol. 44(S18), S94–S105 (2017).
MedlineGoogle Scholar
5. Kassebaum NJ, Bernabé E, Dahiya M, Bhandari B, Murray CJ, Marcenes W. Global burden of severe periodontitis in 1990–2010: a systematic review and meta-regression. J. Dent. Res. 93(11), 1045–1053 (2014).
Medline CASGoogle Scholar
6. Hajishengallis G, Chavakis T. Local and systemic mechanisms linking periodontal disease and inflammatory comorbidities. Nat. Rev. Immunol. 21(7), 426–440 (2021).
Medline CASGoogle Scholar
7. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet 366(9499), 1809–1820 (2005). • Review of periodontal diseases.
MedlineGoogle Scholar
8. Hasan A, Palmer RM. A clinical guide to periodontology: pathology of periodontal disease. Br. Dent. J. 216(8), 457–461 (2014).
Medline CASGoogle Scholar
9. Wade WG. Has the use of molecular methods for the characterization of the human oral microbiome changed our understanding of the role of bacteria in the pathogenesis of periodontal disease? J. Clin. Periodontol. 38(s11), 7–16 (2011).
MedlineGoogle Scholar
10. Abusleme L, Hoare A, Hong BY, Diaz PI. Microbial signatures of health, gingivitis, and periodontitis. Periodontol. 2000 86(1), 57–78 (2021).
MedlineGoogle Scholar
11. Sakamoto M, Umeda M, Benno Y. Molecular analysis of human oral microbiota. J. Periodont. Res. 40(3), 277–285 (2005).
Medline CASGoogle Scholar
12. Caffesse RG, Echeverría JJ. Treatment trends in periodontics. Periodontol. 2000 79(1), 7–14 (2019).
MedlineGoogle Scholar
13. Langer R. New methods of drug delivery. Science 249(4976), 1527–1533 (1990).
Medline CASGoogle Scholar
14. Hecht DW. Prevalence of antibiotic resistance in anaerobic bacteria: worrisome developments. Clin. Infect. Dis. 39(1), 92–97 (2004).
MedlineGoogle Scholar
15. Herrera D, Alonso B, León R, Roldán S, Sanz M. Antimicrobial therapy in periodontitis: the use of systemic antimicrobials against the subgingival biofilm. J. Clin. Periodontol. 35(Suppl. 8), 45–66 (2008).
Medline CASGoogle Scholar
16. Loesche WJ, Giordano JR, Hujoel P, Schwarcz J, Smith BA. Metronidazole in periodontitis: reduced need for surgery. J. Clin. Periodontol. 19(2), 103–112 (1992). • Review of metronidazole in periodontitis.
Medline CASGoogle Scholar
17. Dziedzic A, Wojtyczka RD. Periodontology: antibiotics protocol. Br. Dent. J. 217(12), 660–660 (2014).
Medline CASGoogle Scholar
18. Serbanescu MA, Oveisi M, Sun C, Fine N, Bosy A. Glogauer M Metronidazole enhances killing of Porphyromonas gingivalis by human PMNs. Front. Oral Health 3, 933997 (2022).
MedlineGoogle Scholar
19. Ardila CM, Bedoya-García JA. Antimicrobial resistance of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Tannerella forsythia in periodontitis patients. J. Glob. Antimicrob. Resist. 22, 215–218 (2020).
MedlineGoogle Scholar
20. Tamaki N, Cristina Orihuela-Campos R, Inagaki Y, Fukui M, Nagata T, Ito HO. Resveratrol improves oxidative stress and prevents the progression of periodontitis via the activation of the Sirt1/AMPK and the Nrf2/antioxidant defense pathways in a rat periodontitis model. Free Radic. Biol. Med. 75, 222–229 (2014).
Medline CASGoogle Scholar
21. Wei Y, Deng Y, Ma S et al. Local drug delivery systems as therapeutic strategies against periodontitis: a systematic review. J. Control. Rel. 333, 269–282 (2021). • Review of local drug-delivery systems for periodontitis.
Medline CASGoogle Scholar
22. Cao H, Yang L, Tian R, Wu H, Gu Z, Li Y. Versatile polyphenolic platforms in regulating cell biology. Chem. Soc. Rev. 51(10), 4175–4198 (2022).
Medline CASGoogle Scholar
23. Gómez-Florit M, Monjo M, Ramis JM. Identification of quercitrin as a potential therapeutic agent for periodontal applications. J. Periodontol. 85(7), 966–974 (2014).
Medline CASGoogle Scholar
24. Zhou T, Chen D, Li Q, Sun X, Song Y, Wang C. Curcumin inhibits inflammatory response and bone loss during experimental periodontitis in rats. Acta Odontol. Scand. 71(2), 349–356 (2013).
Medline CASGoogle Scholar
25. López-Valverde N, López-Valverde A, Montero J, Rodríguez C, Macedo de Sousa B, Aragoneses JM. Antioxidant, anti-inflammatory and antimicrobial activity of natural products in periodontal disease: a comprehensive review. Front. Bioeng. Biotechnol. 11, 1226907 (2023).
Google Scholar
26. Hirasawa M, Takada K, Makimura M, Otake S. Improvement of periodontal status by green tea catechin using a local delivery system: a clinical pilot study. J. Periodontal Res. 37(6), 433–438 (2002).
Medline CASGoogle Scholar
27. Shahzad M, Millhouse E, Culshaw S, Edwards CA, Ramage G, Combet E. Selected dietary (poly)phenols inhibit periodontal pathogen growth and biofilm formation. Food Funct. 6(3), 719–729 (2015).
Medline CASGoogle Scholar
28. Tian M, Chen G, Xu J et al. Epigallocatechin gallate-based nanoparticles with reactive oxygen species scavenging property for effective chronic periodontitis treatment. Chem. Eng. J. 433, 132197 (2022).
CASGoogle Scholar
29. Jayusman PA, Nasruddin NS, Mahamad Apandi NI, Ibrahim N, Budin SB. Therapeutic potential of polyphenol and nanoparticles mediated delivery in periodontal inflammation: a review of current trends and future perspectives. Front. Pharmacol. 13, 847702 (2022).
Medline CASGoogle Scholar
30. Lee H, Dellatore SM, Miller WM, Messersmith PB. Mussel-inspired surface chemistry for multifunctional coatings. Science 318(5849), 426–430 (2007).
Medline CASGoogle Scholar
31. Yang P, Gu Z, Zhu F, Li Y. Structural and functional tailoring of melanin-like polydopamine radical scavengers. CCS Chemistry 2(2), 128–138 (2020).
CASGoogle Scholar
32. Kaushik NK, Kaushik N, Pardeshi S, Sharma JG, Lee SH, Choi EH. Biomedical and clinical importance of mussel-inspired polymers and materials. Mar. Drugs 13(11), 6792–6817 (2015).
Medline CASGoogle Scholar
33. Cheng W, Zeng X, Chen H et al. Versatile polydopamine platforms: synthesis and promising applications for surface modification and advanced nanomedicine. ACS Nano 13(8), 8537–8565 (2019).
Medline CASGoogle Scholar
34. Bai B, Gu C, Lu X et al. Polydopamine functionalized mesoporous silica as ROS-sensitive drug delivery vehicles for periodontitis treatment by modulating macrophage polarization. Nano Res. 14(12), 4577–4583 (2021). • Polydopamine-functionalized mesoporous silica nanoparticles harness the antioxidative activity of polydopamine to effectively eliminate excessive reactive oxygen species.
CASGoogle Scholar
35. Bao X, Zhao J, Sun J, Hu M, Yang X. Polydopamine nanoparticles as efficient scavengers for reactive oxygen species in periodontal disease. ACS Nano 12(9), 8882–8892 (2018). •• Polydopamine nanoparticles exhibit high efficiency as scavengers for reactive oxygen species in the context of periodontal disease.
Medline CASGoogle Scholar
36. Zou Y, Wu T, Li N, Guo X, Li Y. Photothermal-enhanced synthetic melanin inks for near-infrared imaging. Polymer 186, 122042 (2020).
CASGoogle Scholar
37. Li Z, Wang T, Zhu F, Wang Z, Li Y. Bioinspired fluorescent dihydroxyindoles oligomers. Chin. Chem. Lett. 31(3), 783–786 (2020).
CASGoogle Scholar
38. Liu H, Qu X, Tan H et al. Role of polydopamine's redox-activity on its pro-oxidant, radical-scavenging, and antimicrobial activities. Acta Biomater. 88, 181–196 (2019). • Review of polydopamine's redox activity.
Medline CASGoogle Scholar
39. Liu Y, Ai K, Ji X et al. Comprehensive insights into the multi-antioxidative mechanisms of melanin nanoparticles and their application to protect brain from injury in ischemic stroke. J. Am. Chem. Soc. 139(2), 856–862 (2017).
Medline CASGoogle Scholar
40. Zhao H, Zeng Z, Liu L et al. Polydopamine nanoparticles for the treatment of acute inflammation-induced injury. Nanoscale 10(15), 6981–6991 (2018).
Medline CASGoogle Scholar
41. Zhang J, Fu Y, Yang P, Liu X, Li Y, Gu Z. ROS scavenging biopolymers for anti-inflammatory diseases: classification and formulation. Adv. Mater. Interfaces 7(16), 2000632 (2020).
CASGoogle Scholar
42. Wang X, Zhao H, Liu Z et al. Polydopamine nanoparticles as dual-task platform for osteoarthritis therapy: a scavenger for reactive oxygen species and regulator for cellular powerhouses. Chem. Eng. J. 417, 129284 (2021).
CASGoogle Scholar
43. Kunrath MF, Shah FA, Dahlin C. Bench-to-bedside: feasibility of nano-engineered and drug-delivery biomaterials for bone-anchored implants and periodontal applications. Mater. Today Bio. 18, 100540 (2023).
Medline CASGoogle Scholar
44. Saadi-Thiers K, Huck O, Simonis P et al. Periodontal and systemic responses in various mice models of experimental periodontitis: respective roles of inflammation duration and Porphyromonas gingivalis infection. J. Periodontol. 84(3), 396–406 (2013).
Medline CASGoogle Scholar
45. Marchesan J, Girnary MS, Jing L et al. An experimental murine model to study periodontitis. Nat. Protoc. 13(10), 2247–2267 (2018).
Medline CASGoogle Scholar
46. Lin P, Niimi H, Ohsugi Y et al. Application of ligature-induced periodontitis in mice to explore the molecular mechanism of periodontal disease. Int. J. Mol. Sci. 22(16), 8900 (2021).
Medline CASGoogle Scholar
47. Abe T, Hajishengallis G. Optimization of the ligature-induced periodontitis model in mice. J. Immunol. Methods 394(1–2), 49–54 (2013).
Medline CASGoogle Scholar
48. Ju KY, Lee Y, Lee S, Park SB, Lee JK. Bioinspired polymerization of dopamine to generate melanin-like nanoparticles having an excellent free-radical-scavenging property. Biomacromolecules 12(3), 625–632 (2011).
Medline CASGoogle Scholar
49. Ali AE, Elasala GS, Ibrahim RS. Synthesis, characterization, spectral, thermal analysis and biological activity studies of metronidazole complexes. J. Mol. Struct. 1176, 673–684 (2019).
CASGoogle Scholar
50. Sczepanik FSC, Grossi ML, Casati M et al. Periodontitis is an inflammatory disease of oxidative stress: we should treat it that way. Periodontol. 2000 84(1), 45–68 (2020).
MedlineGoogle Scholar
51. Wang Y, Andrukhov O, Rausch-Fan X. Oxidative stress and antioxidant system in periodontitis. Front. Physiol. 8, 910 (2017).
MedlineGoogle Scholar
52. Matthews JB, Wright HJ, Roberts A, Cooper PR, Chapple ILC. Hyperactivity and reactivity of peripheral blood neutrophils in chronic periodontitis. Clin. Exp. Immunol. 147(2), 255–264 (2007).
Medline CASGoogle Scholar
53. Buczko P, Zalewska A, Szarmach I. Saliva and oxidative stress in oral cavity and in some systemic disorders. J. Physiol. Pharmacol. 66(1), 3–9 (2015).
Medline CASGoogle Scholar
54. Cheng Z, Meade J, Mankia K, Emery P, Devine DA. Periodontal disease and periodontal bacteria as triggers for rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol. 31(1), 19–30 (2017).
MedlineGoogle Scholar
55. Sui L, Wang J, Xiao Z, Yang Y, Yang Z, Ai K. ROS-scavenging nanomaterials to treat periodontitis. Front. Chem. 8, 595530 (2020).
Medline CASGoogle Scholar
56. Chen E, Wang T, Tu Y et al. ROS-scavenging biomaterials for periodontitis. J. Mater. Chem. B 11(3), 482–499 (2023).
Medline CASGoogle Scholar
57. Iqbal Z, Lai EPC, Avis TJ. Antimicrobial effect of polydopamine coating on Escherichia coli. J. Mater. Chem. 22(40), 21608–21612 (2012).
CASGoogle Scholar
58. Fu Y, Yang L, Zhang J et al. Polydopamine antibacterial materials. Mater. Horizons 8(6), 1618–1633 (2021).
Medline CASGoogle Scholar
59. Su L, Yu Y, Zhao Y, Liang F, Zhang X. Strong antibacterial polydopamine coatings prepared by a shaking-assisted method. Sci. Rep. 6(1), 24420 (2016).
Medline CASGoogle Scholar

Vol. 18, No. 29

Supplemental Materials

Metrics

Downloaded 87 times

History

Received 31 August 2023

Accepted 1 November 2023

Published online 21 December 2023

Published in print December 2023

Information

Keywords

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/nnm-2023-0245

Author contributions

M Yan and W Liang: conceptualization, methodology, validation, formal analysis, investigation and writing of original draft. L Du, R Guo, Y Cao, S Ni, Y Zhong, K Zhang, K Qu and X Qin: methodology and investigation. L Chen and W Wu: conceptualization, resources, methodology, supervision, writing, review and editing.

Acknowledgments

The authors would like to thank the Analysis and Testing Center of Chongqing University for the provision of some large instruments and equipment.

Financial disclosure

This work was supported by the National Natural Science Foundation of China (31971301,32171324), Fundamental Research Funds for the National Key R&D Project (2022YFF0710700), China Postdoctoral Science Foundation (2020M683271, 2022M720574), Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0149, CSTB2022NSCQ-BHX0724, CSTB2022NSCQ-BHX0718), Fundamental Research Funds for Central Universities (2020CDJQY-A061, 2018CDHB1B08). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all animal experimental investigations. All animal procedures were performed in accordance with the Guidelines for Experimental Animal Management Measures of Chongqing University and approved by the Chongqing University Institutional Animal Care and Use Committee (ACUC) (IACUC issue number: COU-IACUC-RE-202109-002).

PDF download