Novel nanomaterial-based antibacterial photodynamic therapies to combat oral bacterial biofilms and infectious diseases

Abstract

Oral diseases such as tooth caries, periodontal diseases, endodontic infections, etc., are prevalent worldwide. The heavy burden of oral infectious diseases and their consequences on the patients' quality of life indicates a strong need for developing effective therapies. Advanced understandings of such oral diseases, e.g., inflammatory periodontal lesions, have raised the demand for antibacterial therapeutic strategies, because these diseases are caused by viruses and bacteria. The application of antimicrobial photodynamic therapy (aPDT) on oral infectious diseases has attracted tremendous interest in the past decade. However, aPDT had a minimal effect on the viability of organized biofilms due to the hydrophobic nature of the majority of the photosensitizers (PSs). Therefore, novel nanotechnologies were rapidly developed to target the delivery of hydrophobic PSs into microorganisms for the antimicrobial performance improvement of aPDT. This review focuses on the state-of-the-art of nanomaterials applications in aPDT against oral infectious diseases. The first part of this article focuses on the cutting-edge research on the synthesis, toxicity, and therapeutic effects of various forms of nanomaterials serving as PS carriers for aPDT applications. The second part discusses nanomaterials applications for aPDT in treatments of oral diseases. These novel bioactive nanomaterials have demonstrated great potential to serve as carriers for PSs to substantially enhance the PDT therapeutic effects. Furthermore, the novel aPDT applications not only have exciting therapeutic potential to inhibit bacterial plaque-initiated oral diseases, but also have a wide applicability to other biomedical and tissue engineering applications.

Keywords: anti-inflammatory; antibacterial; nanomaterials; oral diseases; photodynamic therapy; upconversion nanoparticles.

Figure 1

SOG regulation by aptamer-binding protein. Notes: (A) SOSG signal readout after 10.5 mins of irradiation with excitation at 404 nm. SWNTs showed great quenching for SOG. After introduction of 2.0 μM thrombin, SOG was increased. (B) SOSG signal plotted as a function of Tmb concentration. The purple line indicates the buffer’s SOSG signal. Reprinted with permission from Zhu Z, Tang Z, Phillips JA, Yang R, Wang H, Tan W. Regulation of singlet oxygen generation using single-walled carbon nanotubes. J Am Chem Soc. 2008;130(33):10856–10857. Copyright (2008) American Chemistry Society. Abbreviations: SOG, singlet oxygen generation; SOSG, singlet oxygen sensor green; SWNTs, single-walled carbon nanotubes; Tmb, thrombin.

Figure 2

Confocal microscopy to compare skin penetration efficiency of free Pheo A, DPPC liposomes, and DPP transfersomes. The line scan data are shown by the white arrows in the images. Notes: Cross-sections of (A) normal skin; and (B) P. acnes-induced skin were incubated on a Franz diffusion cell (n=3). The blue signal indicates DAPI (nucleus; excitation/emission: 358/461 nm). The red signal indicates Pheo A (excitation/emission: 410 nm/675 nm). Scale bar = 200 μm. Reprinted with permission from Park H, Lee J, Jeong S, et al. Lipase‐sensitive transfersomes based on photosensitizer/polymerizable lipid conjugate for selective antimicrobial photodynamic therapy of acne. Adv Healthc Mater. 2016;5(24):3139–3147. Copyright (2016) John Wiley and Sons. Abbreviations: DAPI, 4ʹ,6-diamidino-2-phenylinodle; DPP, DSPE-PEG-Pheo A; DPPC, dipalmitoylphosphatidylcholine; P. acnes, Propionibacterium acnes; Pheo A, pheophorbide A.

Figure 3

SEM images of P. aeruginosa after diverse treatment with different durations with or without light irradiation for 30 mins. Reprinted with permission from Xiao F, Cao B, Wang C, et al. Pathogen-specific polymeric antimicrobials with significant membrane disruption and enhanced photodynamic damage to inhibit highly opportunistic bacteria. The yellow arrows in the images showed the obvious membrane damage of the bacteria. ACS Nano. 2019;13(2):1511–1525. Copyright (2019) American Chemistry Society. Abbreviations: P. aeruginosa, Pseudomonas aeruginosa; SEM, scanning electron microscope.

Figure 4

Schematic diagram of the application of aPDT in dentistry. APDT had potential to inhibit many oral infections including caries, endodontic diseases, root canal infections, periodontitis, peri-implantitis, oral fungal infections and maxillofacial infections. Abbreviation: aPDT, antimicrobial photodynamic therapy.

Figure 5

Proposed structures of nanomaterials against dental caries, endodontic infections and periodontal diseases. Notes: (A) TBO-AgNP; (B) GO-Car/HAp@ICG; (C) CSRBnp with EDC and NHS; (D) NGO-ICG; (E) MOF-ICG and antibacterial mechanism; (F) MB-loaded PLGA cationic NPs; (G) antibacterial multifunctional NPs Fe₃O₄-silane@Ce6/C6; and (H) UCNPs@TiO₂ and upconversion processes. Reprinted from Gholibegloo E, Karbasi A, Pourhajibagher M, et al. Carnosine-graphene oxide conjugates decorated with hydroxyapatite as promising nanocarrier for ICG loading with enhanced antibacterial effects in photodynamic therapy against Streptococcus mutans. J Photoch Photobio B. 2018;181:14–22, Copyright (2018), with permission from Elsevier for Figure 5B. Reprinted from Akbari T, Pourhajibagher M, Hosseini F, et al. The effect of indocyanine green loaded on a novel nano-graphene oxide for high performance of photodynamic therapy against Enterococcus faecalis. Photodiagn Photodyn. 2017;20:148–153, Copyright (2017), with permission from Elsevier for Figure 5D. Reprinted with permission from Golmohamadpour A, Bahramian B, Khoobi M, Pourhajibagher M, Barikani HR, Bahador A. Antimicrobial photodynamic therapy assessment of three indocyanine green-loaded metal-organic frameworks against Enterococcus faecalis. Photodiagn Photocyn. 2018;23:331–338. Copyright (2018), with permission from Elsevier for Figure 5E. Abbreviations: AgNP, silver nanoparticle; PS, photosensitizer; Car, carnosine; CSRBnp, rose bengal functionalized chitosan nanoparticles; EDC, N-ethyl-N’-(3-dimethyl aminopropyl) carbodiimide; GO, Graphene oxide; HAp, hydroxyapatite; ICG, indocyanine green; MB, Methylene blue; MOF, metal-organic frameworks; NGO, nano-Graphene oxide; NHS, N-Hydroxysuccinimide; NPs, nanoparticles; PLGA, Poly lactic-co-glycolic acid; TBO, Toluidine blue O; UCNPs, upconversion nanoparticles.

Figure 6

(A) Plate samples showing colonies of E. coli and S. aureus under 660 nm visible light for 20 mins or in the dark. (B) Antibacterial ratio determined according to the number of colonies in the plate samples **P < 0.01 vs Ti group as control. (C) ESR signals of ¹O₂ obtained upon irradiation of different samples for 20 mins in the presence of TEMP. (D) Morphologies of E. coli and S. aureus seeded on MP-Ti and TA/Fe³⁺/AgNPs-10 under the illumination of 660 nm visible light for 20 min (scale bar =1 μm). The red arrows in (D) indicated the portions of the membrane were shrunk, and several parts were completely broken. Reprinted with permission from Xu Z, Wang X, Liu X, et al. Tannic acid/Fe³⁺/Ag nanofilm exhibiting superior photodynamic and physical antibacterial activity. ACS Appl Mater Inter. 2017;9(45):39657–39671. Copyright (2017) American Chemistry Society. Abbreviations: E. coli, Escherichia coli; ESR, electron spin resonance; MP-Ti, mechanically polished Ti plates; S. aureus, Staphylococcus aureus; TEMP, 2,2,6,6-tetramethylpiperidine.

Figure 7

(A–E) Antibacterial effects of OC-UCNP-ZnPc on MDR bacteria in vitro. Viability of (A) MRSA and (B) β-lactamase-producing E. coli after incubation with OC-UCNP-ZnPc at different concentrations with/without NIR irradiation; (C) antibacterial effects induced by the nanoconstructs on MRSA (solid line) and β-lactamase-producing E. coli (dotted line); (D) TEM images, and (E) photographs of plate samples of MRSA in control, OC-UCNP-ZnPc (125 μg mL⁻¹) group without NIR irradiation, 980 nm light-triggered PDT group, and vancomycin (125 μg mL⁻¹) positive control. OC-UCNP-ZnPc nanoconstructs could be observed in TEM of OC-UCNP-ZnPc groups (the red arrows). (F–G) Anti-MRSA efficacy of OC-UCNP-ZnPc nanoconstructs in vivo. (F) Changes in the volume of MRSA-infected skin abscesses; (G) in vivo anti-MRSA efficacy of different groups at day 12. Statistical significance was determined by a Student's t test (##P< 0.01 for the OC-UCNP-ZnPc treatment group and the 980 nm light triggered deep-tissue PDT treatment group compared with the control group; **P< 0.01 for the 980 nm light triggered deep-tissue PDT group compared with the OC-UCNP-ZnPc treatment group without 980 nm light irradiation; ΔP< 0.05 for the 980 nm light triggered deep-tissue PDT group compared with the 660 nm light induced deep-tissue PDT group). Republished with permission of RSC Pub, from Li S, Cui S, Yin D, et al. Dual antibacterial activities of a chitosan-modified upconversion photodynamic therapy system against drug-resistant bacteria in deep tissue. Nanoscale. 2017;9(11):3912–3924. Copyright (2017) Royal Society of Chemistry. Permission conveyed through Copyright Clearance Center, Inc. Abbreviations: E. coli, Escherichia coli; MDR, multi-drug resistant; MRSA, methicillin-resistant Staphylococcus aureus; NIR, near-infrared; OC, N-octyl chitosan; TEM, transmission electron microscope; UCNP, upconversion nanoparticle; ZnPc, zinc phthalocyanine.

Figure 8

(A) Photographs of biofilms. (B) Quantifying the eradication of antibiotic-resistant biofilms by crystal violet staining treatment with various agents (n = 5). (C) Viabilities of HeLa cells vs increasing concentrations of RBS@UCNP@mSiO₂@qC NPs. (D) Synergistic dispersal of biofilms in vivo. (E) Implanted catheters and the surface of embedded catheters observed by SEM. The inset of (E) shows the magnified images. The red arrows indicate the biofilms on the embedded catheters. (F) CFU in vivo in the control and treatment group. (G) Histological analysis of tissues around implants. Each group had 5 rats (n = 5). Republished with permission of Royal Society of Chemistry, from Dong K, Ju E, Gao N, Wang Z, Ren J, Qu X. Synergistic eradication of antibiotic-resistant bacteria based biofilms in vivo using a NIR-sensitive nanoplatform. Chem Commun. 2016;52(30):5312–5315. Permission conveyed through Copyright Clearance Center, Inc. Abbreviations: CFU, colony-forming units; qC, quaternized ammonium chitosan; RBS, Roussin’s black salt; SEM, scanning electron microscope; UCNP, upconversion nanoparticle.