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. 2018 Apr;22(3):1243-1252.
doi: 10.1007/s00784-017-2215-y. Epub 2017 Sep 30.

Doxycycline-loaded nanotube-modified adhesives inhibit MMP in a dose-dependent fashion

Jadesada Palasuk  1   2 , L Jack Windsor  2 , Jeffrey A Platt  2 , Yuri Lvov  3 , Saulo Geraldeli  4 , Marco C Bottino  5
Affiliations

Doxycycline-loaded nanotube-modified adhesives inhibit MMP in a dose-dependent fashion

Jadesada Palasuk et al. Clin Oral Investig. 2018 Apr.

Abstract

Objectives: This article evaluated the drug loading, release kinetics, and matrix metalloproteinase (MMP) inhibition of doxycycline (DOX) released from DOX-loaded nanotube-modified adhesives. DOX was chosen as the model drug, since it is the only MMP inhibitor approved by the U.S. Food and Drug Administration.

Materials and methods: Drug loading into the nanotubes was accomplished using DOX solution at distinct concentrations. Increased concentrations of DOX significantly improved the amount of loaded DOX. The modified adhesives were fabricated by incorporating DOX-loaded nanotubes into the adhesive resin of a commercial product. The degree of conversion (DC), Knoop microhardness, DOX release kinetics, antimicrobial, cytocompatibility, and anti-MMP activity of the modified adhesives were investigated.

Results: Incorporation of DOX-loaded nanotubes did not compromise DC, Knoop microhardness, or cell compatibility. Higher concentrations of DOX led to an increase in DOX release in a concentration-dependent manner from the modified adhesives. DOX released from the modified adhesives did not inhibit the growth of caries-related bacteria, but more importantly, it did inhibit MMP-1 activity.

Conclusions: The loading of DOX into the nanotube-modified adhesives did not compromise the physicochemical properties of the adhesives and the released levels of DOX were able to inhibit MMP activity without cytotoxicity.

Clinical significance: Doxycycline released from the nanotube-modified adhesives inhibited MMP activity in a concentration-dependent fashion. Therefore, the proposed nanotube-modified adhesive may hold clinical potential as a strategy to preserve resin/dentin bond stability.

Keywords: Dental adhesive; Doxycycline; Halloysite®; Matrix metalloproteinase; Nanotubes.

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Conflict of interest statement

Conflict of Interest The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1
Degree of conversion (DC) of the control (SBMP) and modified adhesives that were light-cured for 10, 20 or 40 sec. Increased curing times led to an increase in the DC values: 61.40–64.68% (10 sec), 64.15–68.65% (20 sec), and 70.44–73.26% (40 sec). No significant differences were found in DC (with each curing time) among the groups (p>0.05).
Figure 2
Figure 2
Knoop microhardness number (KHN) of the control (SBMP) and modified adhesives polymerized for 20 sec. KHN was 20.72 ± 1.38 (SBMP), 21.21 ± 0.59 (HNT), 22.18 ± 0.97 (10% DOX), 21.87 ± 2.28 (20% DOX), and 20.89 ± 1.30 (30% DOX). No significant differences were found in Knoop microhardness among the groups (p>0.05).
Figure 3
Figure 3
Cumulative release profile (µg, mean ± SE) of the control (SBMP) and modified adhesives determined by mass spectrometry. No significant differences in total cumulative DOX release were found among 10%, 20%, and 30% DOX (p = 0.259).
Figure 4
Figure 4
Representative images of agar diffusion data of the control (SBMP) and modified adhesive disks against S. mutans (A) and L. casei (B) after 72 h of incubation. The average inhibition zones on S. mutans were 16.0 ± 1.1 mm (0.12% chlorhexidine, CHX), 2.3 ± 3.6 mm (10% DOX), 8.1 ± 0.9 mm (20% DOX), and 11.5 ± 2.6 mm (30% DOX). The average inhibition zones on L. casei were 14.4 ± 0.5 mm (0.12% chlorhexidine), 5.1 ± 4.0 mm (10% DOX), 7.2 ± 3.7 mm (20% DOX), and 11.3 ± 1.8 mm (30% DOX). 0.12% CHX and sterile PBS, served as the positive and negative controls, respectively. No inhibition zones were observed with specimen disks of SBMP, HNT, sterile PBS and DOX-containing eluates of all groups (data not shown). Statistical analysis showed that the inhibition zones on S. mutans and L. casei were statistically significant among 10%DOX, 20%DOX, and 30%DOX, except for the inhibition zone of L. casei, which was between 10%DOX and 20%DOX.
Figure 5
Figure 5
Viability of human dental pulp stem cells (hDPSCs, %). hDPSCs were exposed to eluates of the control (SBMP) and modified adhesive disks. Viability of the cells incubated with various eluates ranged from 81.60% to 107.92% compared to that of the cells not incubated with eluate (100% survival). No significant differences were found among cells incubated with eluates of the same dilution of each group of samples, compared with cells not incubated with eluates.
Figure 6
Figure 6
Inhibition of MMP-1 by DOX-containing eluates (%, mean ± SE) compared to the negative control (Tris buffer). MMP-1 inhibition was gradually diminished over time. Statistical analysis showed a significant difference between 0.1% DOX and each of the samples from various time points. At day 1, eluates of 30% DOX showed significantly higher MMP inhibition than those of the control (SBMP, p<0.05). At day 7, eluates of 10% and 30% DOX showed significantly higher MMP inhibition than those of control (SBMP) and HNT (p<0.05). No other significant differences in MMP-1 inhibition were found among other eluates (p>0.05).
Figure 7
Figure 7
Scanning (A) and transmission (B) electron micrographs at 20,000× and 68,000×, respectively of the nanotubes (HNT, white arrows) used. TEM micrographs of the interface between resin composite (RC) and HNT-modified adhesive at 20,000× (C) and 120000× (D).
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