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. 2020 Dec 11;2(12):5779-5789.
doi: 10.1021/acsapm.0c01031. Epub 2020 Nov 11.

Antimicrobial Nanogels with Nanoinjection Capabilities for Delivery of the Hydrophobic Antibacterial Agent Triclosan

Guangyue Zu  1 , Magdalena Steinmüller  1 , Damla Keskin  1 , Henny C van der Mei  1 , Olga Mergel  1 , Patrick van Rijn  1
Affiliations

Antimicrobial Nanogels with Nanoinjection Capabilities for Delivery of the Hydrophobic Antibacterial Agent Triclosan

Guangyue Zu et al. ACS Appl Polym Mater. .

Abstract

With the ever-growing problem of antibiotic resistance, developing antimicrobial strategies is urgently needed. Herein, a hydrophobic drug delivery nanocarrier is developed for combating planktonic bacteria that enhances the efficiency of the hydrophobic antimicrobial agent, Triclosan, up to a 1000 times. The poly(N-isopropylacrylamide-co-N-[3-(dimethylamino)propyl]methacrylamide), p(NIPAM-co-DMAPMA), based nanogel is prepared via a one-pot precipitation polymerization, followed by quaternization with 1-bromododecane to form hydrophobic domains inside the nanogel network through intraparticle self-assembly of the aliphatic chains (C12). Triclosan, as the model hydrophobic antimicrobial drug, is loaded within the hydrophobic domains inside the nanogel. The nanogel can adhere to the bacterial cell wall via electrostatic interactions and induce membrane destruction via the insertion of the aliphatic chains into the cell membrane. The hydrophobic antimicrobial Triclosan can be actively injected into the cell through the destroyed membrane. This approach dramatically increases the effective concentration of Triclosan at the bacterial site. Both the minimal inhibitory concentration and minimal bactericidal concentration against the Gram-positive bacteria S. aureus and S. epidermidis decreased 3 orders of magnitude, compared to free Triclosan. The synergy of physical destruction and active nanoinjection significantly enhances the antimicrobial efficacy, and the designed nanoinjection delivery system holds great promise for combating antimicrobial resistance as well as the applications of hydrophobic drugs delivery for many other possible applications.

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Conflict of interest statement

The authors declare the following competing financial interest(s): P.v.R also is co-founder, scientific advisor, and share-holder of BiomACS BV, a biomedical oriented screening company.

Figures

Figure 1
Figure 1
Schematic illustration of the main synthesis procedure of the antimicrobial nanogels. The tertiary amine-functionalized nanogel (tA-NG) was synthesized by precipitation polymerization of NIPAM with DMAPMA. The quaternized nanogels (Qcn-NG (n = 1 or 12)) were prepared by functionalization of the tertiary amine group with different alkyl chain lengths of quaternization agents (methyl iodide and 1-bromododecane). Finally, the Triclosan-loaded nanogel (Qc12-NG+T) was obtained by loading the antimicrobial agent Triclosan in the Qc12-NG via the hydrophobic interaction between Triclosan and the hydrophobic cavity inside nanogel networks formed by the alkyl chain (C12).
Figure 2
Figure 2
Fluorescence spectra of (a) Nile Red in the presence of dodecyl-quaternized nanogel Qc12-NG and tertiary amine-functionalized nanogel tA-NG (excitation wavelength: 540 nm) and (b) Triclosan and Triclosan-loaded nanogel Qc12-NG+T (excitation wavelength: 280 nm).
Figure 3
Figure 3
Transmission electron microscopy images of nanogels dried on a carbon-coated copper grid and size distribution by the intensity of nanogels in aqueous media determined by dynamic light scattering analysis in water at 25 °C. (a) Tertiary amine-functionalized nanogel tA-NG, (b) methyl-quaternized nanogel Qc1-NG, (c) dodecyl-quaternized nanogel Qc12-NG, and (d) Triclosan-loaded nanogel Qc12-NG+T (scale bar = 200 nm).
Figure 4
Figure 4
(a) Hydrodynamic radii as a function of temperature obtained from dynamic light scattering measurements for tertiary amine-functionalized nanogel tA-NG, methyl-quaternized nanogel Qc1-NG, and dodecyl-quaternized nanogel Qc12-NG in water. (b) pH-dependent zeta potential of the tA-NG, Qc1-NG, and Qc12-NG in 0.05 M NaCl at 25 °C.
Figure 5
Figure 5
(a) MIC folds reduction and (b) MBC folds reduction of free Triclosan and encapsulated Triclosan in Qc12-NG+T for S. epidermidis ATCC 12228, S. epidermidis HBH 45, S. aureus 5298, and S. aureus ATCC 12600.
Scheme 1
Scheme 1. Schematic Illustration of the Bactericidal Mechanism of Triclosan-Loaded Nanogel
Nanogels interact with the peptidoglycan and cell membrane layers of Gram-positive bacteria via electrostatic interactions (1) and kill the bacteria by puncturing the cell wall and disordering the cytoplasmic membrane (2), followed by the injection of Triclosan from the intraparticle micelles to the bacterial cell membrane and inside the cell (3).
Figure 6
Figure 6
Cell viability in the presence of (a) tertiary amine-functionalized nanogel tA-NG, (b) methyl-quaternized nanogel Qc1-NG, (c) dodecyl-quaternized nanogel Qc12-NG, (d) Triclosan, and (e) Triclosan-loaded nanogel Qc12-NG+T. L929 fibroblasts cells were treated with nanogels and Triclosan for 24, 48, and 72 h at 37 °C, respectively. The cytotoxicity was determined by XTT assay.
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