Toxicology study for magnetic injection of prednisolone into the rat cochlea

Abstract

This paper investigates the safety of a novel 'magnetic injection' method of delivering therapy to the cochlea, in a rodent model. In this method of administration, a magnetic field is employed to actively transport drug-eluting superparamagnetic iron-oxide core nanoparticles into the cochlea, where they then release their drug payload (we delivered the steroid prednisolone). Our study design and selection of control groups was based on published regulatory guidance for safety studies that involve local drug delivery. We tested for both single and multiple delivery doses to the cochlea, and found that magnetic delivery did not harm hearing. There was no statistical difference in hearing between magnetically treated ears versus ears that received intra-tympanic steroid (a mimic of a standard-of-care for sudden sensorineural hearing loss), both 2 and 30 days after treatment. Since our treatment is local to the ear, the levels of steroid and iron circulating systemically after our treatment were low, below mass-spectrometry detection limits for the steroid and no different from normal for iron. No adverse findings were observed in ear tissue histopathology or in animal gross behavior. At 2 and 30 days after treatment, inflammatory changes examined in the ear were limited to the middle ear, were very mild in severity, and by day 90 there was ongoing and almost complete reversibility of these changes. There were no ear tissue scarring or hemorrhage trends associated with magnetic delivery. In summary, after conducting a pre-clinical safety study, no adverse safety issues were observed.

Use of Super Paramagnetic Iron Oxide Nanoparticles as Drug Carriers in Brain and Ear: State of the Art and Challenges

“…Chitosan is a hemocompatible, biocompatible, and hydrophilic polyoside composed of D-glucosamine and N-acetyl-D-glucosamine (a natural cationic linear polymer) and offers active sites for combination with PEG and PEI [ 36 , 40 , 59 , 68 , 87 ]. SPIONs coated with chitosan-PEG copolymer and bearing O 6 -benzylguanine and a targeting peptide, chlorotoxin (NPCP-BG-CTX) were used to potentiate the effect of temozolomide by decreasing the upregulation of the DNA-repair protein O6-methylguanine-DNA methyltransferase (MGMT) [ 68 ].…”

“…Dexamethasone has potential indications in sudden sensorineural hearing loss, Ménière’s disease and other inflammatory conditions of the inner ear such as autoimmune diseases [ 21 , 22 ]. SPIONs combined to dexamethasone administered into the perilymphatic space through the round window show no toxicity in rats and guinea pigs as judged by hearing levels and histological observations [ 79 , 87 ]. Dexamethasone coupled to 500 nm SPIONs could diffuse to the inner ear through an intact RWM [ 79 ].…”

“…SPIONs coated with a rhamnose derivative on 2 GBM cell lines (T98G and U251) and other tumor cells such as human urinary bladder carcinoma cell line (ECV304) and fibroblast cell line (BALB/3T3) showed an increased cellular uptake and dose-dependent cell death after incubation for 24 h (e.g., for T98G cells: 12% of death at 1 µg.Fe −1 .mL versus 35% at 100 µg.Fe −1 .mL) [109]. Chitosan is a hemocompatible, biocompatible, and hydrophilic polyoside composed of D-glucosamine and N-acetyl-D-glucosamine (a natural cationic linear polymer) and offers active sites for combination with PEG and PEI [36,40,59,68,87]. SPIONs coated with chitosan-PEG copolymer and bearing O 6 -benzylguanine and a targeting peptide, chlorotoxin (NPCP-BG-CTX) were used to potentiate the effect of temozolomide by decreasing the upregulation of the DNA-repair protein O6-methylguanine-DNA methyltransferase (MGMT) [68].…”

Drug Delivery across Barriers to the Middle and Inner Ear

“…There was only a mild and transient effect on hearing (assessed by acoustic brain response) from the therapy, and inflammation was mild and limited to the middle ear. [76]…”

Inner ear delivery: Challenges and opportunities

“…These SPIONs cause minimal inflammatory response. Application of nanoparticles with iron oxide cores in a chitosan matrix loaded with prednisolone was not associated with a difference in hearing loss at 2 and 30 days after treatment, compared to the application of prednisolone alone . Very mild inflammatory changes limited to the middle ear were observed at 2 and 30 days after treatment, with almost complete reversibility of changes by day 90.…”