Development of thermosensitive poloxamer 407-based microbubble gel with ultrasound mediation for inner ear drug delivery

Abstract

Our previous study first investigated feasibility of applying ultrasound (US) and microbubbles (MBs) via external auditory canal to facilitate drug delivery into inner ear. However, most drugs are in aqueous formulae and eliminated via Eustachian tubes after drug application. In this study, feasibility of sustained release of thermosensitive poloxamer 407 (P407)-based MB gel for US mediation-enhanced inner ear drug (dexamethasone, DEX) delivery was investigated. The sol-to-gel transition temperature showed that mixture of DEX and only 10% and 12.5% P407 in MBs can be used for in vitro and in vivo drug delivery experiments. In in vitro Franz diffusion experiments, the release rates of 12.5% P407-MBs þ US groups in the model using DEX as the delivered reagent at 3 h resulted in values 1.52 times greater than those of 12.5% P407-MBs groups. In guinea pigs, by filling tympanic bulla with DEX in 12.5% P407-MBs (DEX-P407-MBs), USMB applied at post-treatment days 1 and 7 induced 109.13% and 66.67% increases in DEX delivery efficiencies, respectively, compared to the group without US. On the 28th day after US-mediated P407-MB treatment, the safety assessment showed no significant changes in the hearing thresholds and no damage to the integrity of cochlea or middle ear. These are the first results to demonstrate feasibility of US-modified liquid form DEX-P407-MB cavitation for enhancing permeability of round window membrane. Then, a gel form of DEX-P407-MBs was generated and thus prolonged the release of DEX in middle ear to maintain the therapeutic DEX level in inner ear for at least 7 days.

Drug delivery systems for treatment of temporomandibular joint osteoarthritis

“…Poloxamer 407, also referred to as Pluronic F-127, has good biocompatibility and is widely used as a drug delivery vehicle (Moura et al, 2020;Liao et al, 2021). It is reported that PEO-PPO-PEO hydrogel Pluronic F127 can load recombinant adenoassociated virus (rAAV) vectors overexpressing the chondrogenic sox9 transcription factor (rAAV-FLAG-hsox9), which form an injectable and thermosensitive therapeutic Frontiers in Pharmacology frontiersin.org hydrogel capable of sustained release of rAAV-FLAG-hsox9 (Madry et al, 2020).…”

Sonoporation of the Round Window Membrane on a Sheep Model: A Safety Study

“…Recently, the permeabilization of RWM to fluorescent markers (Biotin-FITC, Texas-red-labelled gentamicin) or therapeutic molecules (plasmid DNA, dexamethasone, and insulin growth factor 1) using sonoporation has been successfully reported in vitro and in guinea pig models [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. These studies described acoustic protection when applying dexamethasone [ 28 , 31 ] and a better uptake by vestibular hair cells when applying gentamicin [ 29 ].…”

“…Recently, the permeabilization of RWM to fluorescent markers (Biotin-FITC, Texas-red-labelled gentamicin) or therapeutic molecules (plasmid DNA, dexamethasone, and insulin growth factor 1) using sonoporation has been successfully reported in vitro and in guinea pig models [ 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. These studies described acoustic protection when applying dexamethasone [ 28 , 31 ] and a better uptake by vestibular hair cells when applying gentamicin [ 29 ]. The efficiency of acoustically mediated drug delivery depends on the application route of ultrasound (e.g., transcanal or transcranial) and ultrasound parameters, including the central frequency, the duty cycle, the acoustic intensities, and the exposure time [ 29 , 30 ].…”

Prolonged Dexamethasone Exposure Enhances Zebrafish Lateral-Line Regeneration But Disrupts Mitochondrial Homeostasis and Hair Cell Function

“…One limitation to this approach is that dexamethasone is rapidly cleared from the middle ear [ 7 ]. Thus, strategies to provide sustained delivery of dexamethasone to the inner ear are an active area of research [ 8 , 9 ]. While retention of synthetic glucocorticoids in the ear may provide greater therapeutic benefits, the effects of prolonged dexamethasone exposure on hair cell organ homeostasis and function are not well defined.…”