Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model

Hong, Michelle K.; Echanique, Kristen A; Hoffman, Larry F.; Kita, Ashley E.

doi:10.1097/mao.0000000000003839

Cited by 3 publications

(10 citation statements)

References 47 publications

(88 reference statements)

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“…The average diameter of PLGA microparticles was smaller than that of PCL. The PLGA microparticles were intentionally fabricated to be larger than those previously reported by our laboratory (3–4 μm vs. 1 μm) in an effort to encapsulate more NAC and prolong elution, but this did not appear to significantly change the release profile 14 …”

Section: Discussionmentioning

confidence: 99%

“…The PLGA microparticles were intentionally fabricated to be larger than those previously reported by our laboratory (3-4 μm vs. 1 μm) in an effort to encapsulate more NAC and prolong elution, but this did not appear to significantly change the release profile. 14 Since PCL microparticles had the longest sustained release, it is likely that their larger microparticle size allowed for more encapsulation of NAC and a longer duration of release as the microparticle degraded. For future in vivo applications, PCL microparticles would be more suitable.…”

Section: Designing a Methods Of Prolonging N-acetylcysteine Delivery ...mentioning

confidence: 99%

“…Other studies have investigated antioxidants that blunt the effects of cisplatin ototoxicity 10,11 . Thus, an antioxidant like N‐acetylcysteine (NAC) was hypothesized to counteract the influence of oxidative stressors 12–14 . A model of Schwann cell injury was then developed to investigate the protective effects of this antioxidant therapeutic.…”

Section: Introductionmentioning

confidence: 99%

“…Eluted solution was collected by exchanging the 1.5 mL of PBS below the transwell containing microparticles and placing this within cryotubes stored at À20 C. This was done daily for the first 5 days then twice weekly for the first month and weekly thereafter. The concentration of NAC in the eluted solution was determined via linear regression following incubation with Ellman's reagent, a compound that reacts with sulfhydryl groups to induce a color change that is then read on a plate reader at 412 nm 14. RSC96 cells were plated in 96-well plates at a density of 4000 cells/well for 24 h and then co-dosed with cisplatin and resuspended NAC or eluted NAC solutions from 50:50 PLGA and PCL microparticles.…”

mentioning

confidence: 99%

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N‐acetylcysteine microparticles reduce cisplatin‐induced RSC96 Schwann cell toxicity

Kedeshian,

Hong,

Hoffman

et al. 2024

Laryngoscope Investig Oto

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ObjectivesCisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin‐induced demyelination of spiral or Scarpa's ganglion neurons may play an additional role in drug‐induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin‐induced Schwann cell injury and investigates the ability of the antioxidant N‐acetylcysteine to promote Schwann cell viability. A local delivery system of drug‐eluting microparticles was then fabricated, characterized, and investigated for bioactivity.MethodsRSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC50). In subsequent experiments, RSC96 cells were co‐treated with cisplatin and both resuspended or eluted N‐acetylcysteine. Cell viability was assessed with the CCK8 assay.ResultsThe LC50 dose of cisplatin was determined to be 3.76 μM (p = 2.2 x 10−16). When co‐dosed with cisplatin and a therapeutic concentration of resuspended or eluted N‐acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone.ConclusionRSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N‐acetylcysteine improved cell viability and mitigated this injury. N‐acetylcysteine was packaged into microparticles and eluted N‐acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin‐induced ototoxicity.Level of EvidenceN/A Laryngoscope, 2023.

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Section: Discussionmentioning

confidence: 99%

Section: Designing a Methods Of Prolonging N-acetylcysteine Delivery ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

N‐acetylcysteine microparticles reduce cisplatin‐induced RSC96 Schwann cell toxicity

Kedeshian,

Hong,

Hoffman

et al. 2024

Laryngoscope Investig Oto

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“…11,12 Thus, an antioxidant like N-acetylcysteine (NAC) was hypothesized to counteract the influence of oxidative stressors. [13][14][15] A model of Schwann cell injury was then developed to investigate the protective effects of this antioxidant therapeutic.…”

Section: Introductionmentioning

confidence: 99%

N-acetylcysteine Microparticles Reduce Cisplatin-induced RSC96 Schwann Cell Toxicity

Kedeshian,

Hong,

Hoffman

et al. 2023

Preprint

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ObjectivesCisplatin is known to cause inner ear dysfunction. There is growing evidence that cisplatin-induced demyelination of spiral or Scarpa’s ganglion neurons may play an additional role in drug-induced ototoxicity alongside afferent neuron injury. As Schwann cells produce myelin, there may be an opportunity to reduce ototoxic inner ear damage by promoting Schwann cell viability. This work describes a cellular model of cisplatin-induced Schwann cell injury and investigates the ability of the antioxidant N-acetylcysteine to promote Schwann cell viability. A local delivery system of drug-eluting microparticles was then fabricated, characterized, and investigated for bioactivity.MethodsRSC96 rat Schwann cells were dosed with varying concentrations of cisplatin to obtain a dose curve and identify the lethal concentration of 50% of the cells (LC50). In subsequent experiments, RSC96 cells were co-treated with cisplatin and both resuspended or eluted N-acetylcysteine. Cell viability was assessed with the CCK8 assay.ResultsThe LC50dose of cisplatin was determined to be 3.76 μM (p=2.2 × 10−16). When co-dosed with cisplatin and therapeutic concentration of resuspended or eluted N-acetylcysteine, Schwann cells had an increased viability compared to cells dosed with cisplatin alone.ConclusionRSC96 Schwann cell injury following cisplatin insult is characterized in this in vitro model. Cisplatin caused injury at physiologic concentrations and N-acetylcysteine improved cell viability and mitigated this injury. N-acetylcysteine was packaged into microparticles and eluted N-acetylcysteine retained its ability to increase cell viability, thus demonstrating promise as a therapeutic to offset cisplatin-induced ototoxicity.Lay SummaryCisplatin is a chemotherapeutic agent known to cause balance and hearing problems through damage to the inner ear. This project explored cisplatin injury in a Schwann cell culture model and packaged an antioxidant into microparticles suitable for future drug delivery applications.

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An in vitro model for postoperative cranial nerve dysfunction and a proposed method of rehabilitation with N-acetylcysteine microparticles

Kita,

Kedeshian,

Hong

et al. 2024

Eur Arch Otorhinolaryngol

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Purpose When operating near cranial motor nerves, transient postoperative weakness of target muscles lasting weeks to months is often observed. As nerves are typically intact at a procedure’s completion, paresis is hypothesized to result from a combination of neurapraxia and axonotmesis. As both neurapraxia and axonotmesis involve Schwann cell injury and require remyelination, we developed an in vitro RSC96 Schwann cell model of injury using hydrogen peroxide (H2O2) to induce oxidative stress and investigated the efficacy of candidate therapeutic agents to promote RSC96 viability. As a first step in developing a long-term local administration strategy, the most promising of these agents was incorporated into sustained-release microparticles and investigated for bioactivity using this assay. Methods The concentration of H2O2 which reduced viability by 50% was determined to establish a standard for inducing oxidative stress in RSC96 cultures. Fresh cultures were then co-dosed with H2O2 and the potential therapeutics melatonin, N-acetylcysteine, resveratrol, and 4-aminopyridine. Schwann cell viability was evaluated and the most efficacious agent, N-acetylcysteine, was encapsulated into microparticles. Eluted samples of N-acetylcysteine from microparticles was evaluated for retained bioactivity. Results 100 µM N-acetylcysteine improved the viability of Schwann cells dosed with H2O2. 100 µM Microparticle-eluted N-acetylcysteine also enhanced Schwann cell viability. Conclusion We developed a Schwann cell culture model of iatrogenic nerve injury and used this to identify N-acetylcysteine as an agent to promote recovery. N-acetylcysteine was packaged into microparticles and demonstrated promise as a locally administrable agent to reduce oxidative stress in Schwann cells.

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Designing a Prolonged Method of Therapeutic Delivery to Support Rehabilitation From Ototoxic Damage in a Schwann Cell Model

Cited by 3 publications

References 47 publications

N‐acetylcysteine microparticles reduce cisplatin‐induced RSC96 Schwann cell toxicity

N‐acetylcysteine microparticles reduce cisplatin‐induced RSC96 Schwann cell toxicity

N-acetylcysteine Microparticles Reduce Cisplatin-induced RSC96 Schwann Cell Toxicity

An in vitro model for postoperative cranial nerve dysfunction and a proposed method of rehabilitation with N-acetylcysteine microparticles

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