Dexamethasone for Inner Ear Therapy: Biocompatibility and Bio-Efficacy of Different Dexamethasone Formulations In Vitro
Abstract
:1. Introduction
2. Materials and Methods
2.1. Dexamethasone Formulations
2.2. Cell Lines and Culture Conditions
2.2.1. Biocompatibility Test
2.2.2. Bio-Efficacy
2.2.3. TNF-α Detection
2.2.4. Statistical Analysis
3. Results
3.1. Cell Viability for Biocompatibility
3.2. Bio-Efficiency Evaluation by TNF-α Detection
4. Discussion
5. Conclusions
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
CI | Cochlear implant |
DEX-lab | Dexamethasone—laboratory grade |
DEX-med | Dexamethasone—medical grade |
DPS-med | Dexamethasone dihydrogen phosphate-disodium—medical grade |
DPS-lab | Dexamethasone sodium phosphate—laboratory grade |
DMEM | Dulbecco’s modified Eagle’s medium |
ELISA | Enzyme-Linked Immunosorbent Assay |
FCS | Fetal calf serum |
FBs | NIH/3T3 mouse fibroblasts |
h | hour |
HL | Hearing loss |
i.c. | Intracochlear |
i.p. | Intraperitoneal |
i.t. | Intratympanic |
i.v. | Intravenous |
LPS | Lipopolysaccharides |
MTT | 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide |
NC | Negative control |
OD | Optical density |
PC | Positive control |
RT | Room temperature |
SSNHL | Sudden sensorineural hearing loss |
SGN | Spiral ganglion neurons |
SD | Standard deviation |
TNF-α | Tumor necrosis factor alpha |
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Abbreviation | Formula | Molecular Weight(g/mol) | CAS-No. | Manufacturer, Article-No. | Comment |
---|---|---|---|---|---|
DEX-med | C22H29FO5 | 392.46 | 50-02-2 | Caesar & Loretz GmbH, Hilden, Germany; 2211 | Recipe substance for pharmaceutical formulations or active pharmaceutical ingredients; powder |
DEX-lab | C22H29FO5 | 392.46 | 50-02-2 | Sigma-Aldrich, St. Louis, MO, USA; PHR1526 | Laboratory chemical; powder |
DPS-med | C22H28FNa2O8P | 516.4 | 50-02-2 | MerckSerono, Darmstadt, Germany; 7880135315 | Fortecortin® Inject 4 mg; approved drug, solution |
DPS-lab | C22H28FNa2O8P | 516.4 | 2392-39-4 | Sigma-Aldrich, St. Louis, MO, USA; D0720000 | Laboratory chemical, manufactural substances; powder |
DEX Formulation | ||||
---|---|---|---|---|
Concentration | DEX-Med, DEX-Lab; 392.46 g/mol | DPS-Med, DPS-Lab; 516.4 g/mol | ||
µM | mg/mL | µg/mL | mg/mL | µg/mL |
0.03 | 1.18 × 10−5 | 0.0118 | 1.55 × 10−5 | 0.0155 |
0.3 | 1.18 × 10−4 | 0.1177 | 1.55 × 10−4 | 0.1549 |
3 | 1.18 × 10−3 | 1.177 | 1.55 × 10−3 | 1.5492 |
30 | 1.18 × 10−2 | 11.77 | 1.55 × 10−2 | 1.5492 |
60 | 2.36 × 10−2 | 23.55 | 3.10 × 10−2 | 30.984 |
150 | 5.89 × 10−2 | 23.55 | 7.75 × 10−2 | 77.46 |
300 | 0.118 | 117.74 | 0.155 | 154.92 |
600 | 0.235 | 235.48 | 0.310 | 154.92 |
900 | 0.353 | 353.21 | 0.465 | 464.76 |
1000 | 0.392 | 392.46 | 0.516 | 516.4 |
2000 | 0.784 | 784.92 | 1.03 | 1032.8 |
4000 | 1.60 | 1569.84 | 2.07 | 2065.6 |
8000 | 3.14 | 3139.68 | 4.13 | 4131.2 |
10,000 | 3.92 | 3924.6 | 5.16 * | 5164 * |
Concentration (µM) | ||||||||
---|---|---|---|---|---|---|---|---|
0.03–300 | 600 | 900 | 1000 | 2000 | 4000 | 8000 | 10,000 | |
DEX-lab | n.s. | 0.9998 | 0.9546 | 0.0562 | 0.0990 | 0.0140 | 0.0024 | 0.0013 |
DEX-med | n.s. | 0.9994 | 0.4153 | 0.6045 | 0.6919 | 0.0293 | 0.0053 | 0.0014 |
DPS-lab | n.s. | 0.8198 | 0.0926 | <0.0001 | <0.0001 | <0.0001 | <0.0001 | <0.0001 |
DPS-med | n.s. | 0.9161 | 0.9997 | 0.7436 | <0.0001 | <0.0001 | <0.0001 | - |
Dexamethasone Formulation, Molecular Weight | Reference | Study Type | Delivery Method | Concentration (mg/mL) * | Remarks |
---|---|---|---|---|---|
DEX-lab, 392.46 g/mol | Connolly et al., 2011 [24] | In vivo | i.v. prior to CI | 0.0002; 0.002 | Lower dose failed to maintain ABR thresholds. High-dose treatment resulted in a reduction of ABR threshold shift. |
Kuthubutheen et al., 2014 [6] | In vivo | i.p. | 0.002 | Spiral ganglion neuron (SGN) density was increased compared to traumatized controls. | |
Jia et al., 2016 [32] | In vitro; in vivo | explants; pump based delivery (1 µL/h, 7 days); | 0.00117; 0.0117; 0.117; 0.117 | In vitro: 0.00117 and 0.0117 mg/mL start to have toxic effects on outer hair cells, 0.117 mg/mL is toxic for inner and outer hair cells; in vivo: 0.117 mg/mL is toxic for SGN but improves ABR thresholds at selected frequencies. | |
Takeda et al., 2021 [14] | In vivo | i.p. | 0.002 | No effect. | |
DEX-med, 392.46 g/mol | Serrano Cardona et al., 2013 [38] | Clinical | DEX in PLGA polymer | 0.7 | Mean hearing threshold improved. |
Bas et al., 2016 [26] | In vivo | DEX in CI silicone; 0.1% = 13 ng/day, 1.0% = 60 ng/day and 10% = 161 ng/day | 1; 10; 100 | 10% and 1.0% protected against electrode insertion-induced HC loss, but increased ABR and CAP thresholds and impedance, fibrosis and loss of cochlear nerve elements. | |
Wilk et al., 2016 [22] | In vivo | DEX in CI silicone (16 ng/day and 49 ng/day) | 10; 100 | Reduced impedances and fibrous tissue growth; increased hearing thresholds. | |
Scheper et al., 2017 [30] | In vivo | DEX in CI silicone (16 ng/day and 49 ng/day; i.e., 0.66 ng/h and 2.04 ng/h) | 10; 100 | Normal SGN number and increased soma diameter. | |
Ahmadi et al., 2019 [39] | In vivo | 6% DEX loaded hydrogel and DEX containing CI | 60 | Auditory nerve fiber protection. | |
DPS-lab, 516.40 g/mol | James et al., 2008 [40] | In vivo | i.t.; 5 µL of 2% | 20 | Residual hearing preservation. |
Souter et al., 2009 [41] | In vivo | i.t., 20% in sponge | 200 | Hearing protection at lower concentrations. | |
Hütten et al., 2014 [27] | In vitro, In vivo | StarPEG-hydrogel filled reservoir, (50 µg DEX/µL hydrogel, 0.35 μg DEX/h) | 50; 50 | Hearing protection, reduced fibrosis. | |
Alexander et al., 2015 [42] | Clinical | DEX i.t., four injections in two weeks | 10; 24 | Recovery of hearing threshold after SSNHL. | |
Scheper et al., 2017 [30] | In vivo | StarPEG-hydrogel filled reservoir, (50 µg DPS-lab/µL hydrogel, 0.35 μg DEX/h) | 50 | Biocompatible regarding SGN number and soma diameter. | |
Lyu et al., 2018 [43] | In vivo | i.c., i.t. and i.p. | 5; 5; 0.01 | 5 but not 0.01 mg/mL preserved hearing in cochlear implanted animals. | |
Ahmadi et al., 2018 [39] | Clinical | Temporarily implanted catheter (4 mg/mL/day) | 4 | No effect. | |
DPS-med, 516.40 g/mol | Coimbra et al., 2007 [44] | In vivo | i.p. every 8 h | 0.0007 | Not effective in preventing neuron loss in pneumococcal meningitis-induced hearing loss. |
Berjis et al., 2016 [9] | Clinical | i.t. (4 mg/mL/day) | 4 | Hearing improvement. | |
Scheper et al., 2017 [30] | In vivo | osmotic pump (25 pg/h) | 0.0001 | Biocompatible regarding SGN number, decreased soma diameter; with electrical stimulation: increased SGN number. |
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Gao, Z.; Schwieger, J.; Matin-Mann, F.; Behrens, P.; Lenarz, T.; Scheper, V. Dexamethasone for Inner Ear Therapy: Biocompatibility and Bio-Efficacy of Different Dexamethasone Formulations In Vitro. Biomolecules 2021, 11, 1896. https://doi.org/10.3390/biom11121896
Gao Z, Schwieger J, Matin-Mann F, Behrens P, Lenarz T, Scheper V. Dexamethasone for Inner Ear Therapy: Biocompatibility and Bio-Efficacy of Different Dexamethasone Formulations In Vitro. Biomolecules. 2021; 11(12):1896. https://doi.org/10.3390/biom11121896
Chicago/Turabian StyleGao, Ziwen, Jana Schwieger, Farnaz Matin-Mann, Peter Behrens, Thomas Lenarz, and Verena Scheper. 2021. "Dexamethasone for Inner Ear Therapy: Biocompatibility and Bio-Efficacy of Different Dexamethasone Formulations In Vitro" Biomolecules 11, no. 12: 1896. https://doi.org/10.3390/biom11121896