Otoprotective properties of 6α-methylprednisolone-loaded nanoparticles against cisplatin: In vitro and in vivo correlation

Abstract

Esta es la versión de autor del artículo publicado en: This is an author produced version of a paper published in: Nanomedicine: Nanotechnology, Biology and Medicine 12.4 (2016) Abstract 6α-Methylprednisolone-loaded surfactant-free nanoparticles have been developed to palliate cisplatin ototoxicity. Nanoparticles were based on two different amphiphilic pseudo-block copolymers obtained by free radical polymerization and based on N-vinyl pyrrolidone and a methacrylic derivative of α-tocopheryl succinate or α-tocopherol. Copolymers formed spherical nanoparticles by nanoprecipitation in aqueous media that were able to encapsulate 6α-methylprednisolone in their inner core. The obtained nanovehicles were tested in vitro using HEI-OC1 cells and in vivo in a murine model. Unloaded nanoparticles were not able to significantly reduce the cisplatin ototoxicity. Loaded nanoparticles reduced cisplatin-ototoxicity in vitro being more active those based on the methacrylic derivative of vitamin E, due to their higher encapsulation efficiency. This formulation was able to protect hair cells in the base of the cochlea, having a positive effect in the highest frequencies tested in a murine model. A good correlation between the in vitro and the in vivo experiments was found.Background Cisplatin (CDDP) is a highly effective chemotherapeutic agent against a variety of solid tumors including head and neck, lungs, ovary, bladder and testicles; however, it presents severe side-effects. Marullo et al1 described a double way of CDDP-induced cytotoxicity: CDDP binding to guanine bases on nuclear DNA and the formation of inter-and intra-strand chain crosslinking trigger cell apoptosis because of replication and transcription blockage; CDDP also has a direct effect on mitochondrial DNA resulting in the impairment of electron 32 transport chain protein synthesis leading to ROS generation. Increasing doses incorporated into protocols, with the aim of increasing cure rates, are related with serious adverse effects that affect kidney function, nervous system and hearing. CDDP induces apoptosis of inner ear cell by binding to DNA, reactive oxygen species (ROS) generation, increased lipid peroxidation and Ca 2+ influx, and inflammation events.2 Hearing impairment begins in the high frequencies and progresses to midrange when patient receives doses higher than 100 mg/m 2. Patients who receive ultrahigh doses of CDDP (150-225 mg/m 42 2), show hearing loss in the high and extended high frequencies in 100% of cases. 44 3 There is substantial variability in susceptibility to the ototoxic effects of CDDP. Rapid intravenous bolus injections, high cumulative doses, pre-existing hearing loss, renal insufficiency, anemia, hypoalbuminemia, and prior cranial irradiation are some of the factors that can play a role in CCDP toxicity. The incidence and severity of hearing loss

Solid Lipid Nanoparticles Loaded with Glucocorticoids Protect Auditory Cells from Cisplatin-Induced Ototoxicity

“…In this context, drug delivery formulations based on hydrogels and nanoparticles have been explored [11,12,13]. Nanoparticles of different chemical natures have been tested for their potential to cross the round window membrane and their capacity to biodegrade [14], including synthetic, amphiphilic, polymeric nanoparticles covalently linked to drugs or interfering RNAs [15,16,17,18]. Lipid nanoparticles are biodegradable and can deliver both hydrophilic and lipophilic drugs depending on their geometry and composition [19,20].…”

Current Strategies to Combat Cisplatin-Induced Ototoxicity

“…Each have a different capacity to reduce cisplatin-induced ototoxicity. For example, Martin-Saldana ( Martin-Saldana et al., 2016 ) designed an NP that not only encapsulated a functional drug (methylprednisolone) but also was active in itself as the NP was constructed of a methacrylic derivatives of α-tocopherol (vitamin E). Biodegradable and biocompatible solid lipid nanoparticles (SLNs) are able to increase glucocorticoid dose to the inner ear, improving protection ( Cervantes et al., 2019 ).…”

Nanomedicine for Inner Ear Diseases: A Review of Recent In Vivo Studies

“…In both studies, administration of dexamethasone-loaded nanoparticles protected hearing in the 4 kHz and 8 kHz frequencies. In another study in which 6 α -methylprednisolone was loaded onto nanoparticles using alpha-tocopherol derivatives, cisplatin-induced hearing loss was protected at 10, 14, and 16 kHz [ 24 ].…”