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Updated: Feb 28, 2026
Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity
Published on: March 16, 2018
siRNA-loaded biodegradable nanocarriers for therapeutic MAPK1 silencing against cisplatin-induced ototoxicity
Ibrahima Youm1, Matthew B West1, Wei Li1
1Hough Ear Institute, Oklahoma City, OK, USA.
Abstract:
Ototoxicity represents a major adverse side-effect of cis-diamminedichloroplatinum-II (cisplatin, CDDP). The mitogen-activated protein kinase (MAPK) pathway is thought to play a central role in potentiating the apoptotic effect of CDDP within the cochlea. We hypothesized that prophylactic inhibition of MAPK signaling, using small interfering RNA (siRNA), might confer a protective effect against CDDP-induced apoptosis within the auditory sensory epithelia. To enhance the therapeutic utility of this approach, we synthesized biocompatible siMAPK1-loaded nanoparticles (NPs) and performed physicochemical characterizations for size, morphology, drug loading and release kinetics, using dynamic light scattering, electron microscopy and spectrophotometric analyses, respectively. Our findings show 183.88±6.26 nm-sized spherical siMAPK1-loaded NPs with -27.12±6.65mV zeta potential and 112.78±0.24pmol/mg of siMAPK1 loading that exhibit a sustained release profile for prolonged therapeutic efficacy. Synthesized NPs were validated for biocompatibility and prophylactically protected against CDDP-induced cytotoxicity in HEI-OC1 cells and hair cell loss in murine organotypic cochlear explants. Our study confirms a pivotal role for MAPK1 signaling as a potentiating factor for CDDP-induced apoptosis and cochlear hair cell loss, and highlights siMAPK1 NP treatment as a therapeutic strategy for limiting the ototoxic side-effects associated with systemic CDDP administration.
Insights
Cisplatin chemotherapy causes ototoxicity by inducing apoptosis in cochlear cells. Inhibiting the MAPK pathway with siMAPK1 nanoparticles protects against this damage, offering a potential strategy to reduce cisplatin
Area of Science:
- Biomedical Engineering
- Ototoxicity Research
- Nanomedicine
Background:
- Cisplatin (CDDP) chemotherapy is associated with significant ototoxicity, a major dose-limiting side effect.
- The mitogen-activated protein kinase (MAPK) pathway is implicated in mediating CDDP-induced apoptosis in cochlear hair cells.
Purpose of the Study:
- To investigate the potential of prophylactic inhibition of MAPK signaling via siRNA to protect against cisplatin-induced ototoxicity.
- To develop and characterize siMAPK1-loaded nanoparticles (NPs) for enhanced therapeutic delivery and efficacy.
Main Methods:
- Synthesis and physicochemical characterization (size, morphology, drug loading, release kinetics) of siMAPK1-loaded NPs.
- In vitro assessment of NP biocompatibility and protective effects against CDDP-induced cytotoxicity in HEI-OC1 cells.
- In vivo validation using murine organotypic cochlear explants to evaluate protection against hair cell loss.
Main Results:
- Spherical siMAPK1 NPs (183.88±6.26 nm) with high loading capacity (112.78±0.24 pmol/mg) and sustained release were successfully synthesized.
- Biocompatible NPs demonstrated prophylactic protection against CDDP-induced cytotoxicity in cell cultures.
- siMAPK1 NP treatment significantly reduced hair cell loss in cochlear explants exposed to CDDP.
Conclusions:
- MAPK1 signaling plays a critical role in potentiating CDDP-induced apoptosis and subsequent cochlear hair cell loss.
- siMAPK1-loaded nanoparticles represent a promising therapeutic strategy for mitigating the ototoxic side effects of cisplatin chemotherapy.
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