geranylgeranylacetone and Hearing-Loss

Prevention of hair cell death is an important target for the prevention of hearing loss. Here, we report the engineering of biodegradable poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) decorated with triphenylphosphonium (TPP) cations as a robust mitochondrial delivery platform, with the aim of preserving mitochondrial integrity and shutting off the initiation of cell death. Geranylgeranylacetone (GGA), a 70 kDa heat shock protein (HSP70) inducer, was used as a therapeutic molecule to attenuate gentamicin (Gen) induced hearing loss. The diameter of the mitochondria-targeting NPs is 145 nm and the encapsulation efficiency is 80.6%. Lysosomal escape and mitochondrial targeting studies indicated the promising therapeutic potential of TPP modified NPs. Finally, the zebrafish lateral line model was applied to verify the efficacy of the GGA loaded targeting NPs for preventing gentamicin-induced death hair cell. The results showed that the prepared targeted NPs provided significant protection: the survival of hair cells increased from 36% to 69% under acute exposure and from 20% to 62% under chronic exposure. In addition, targeted NPs exhibited significantly improved efficiency in alleviating gentamicin-induced hair cell damage compared with free drugs and untargeted NPs, supporting the hypothesis of mitochondrial targeting delivery in the treatment of aminoglycoside-induced hearing loss. These TPP modified NPs demonstrated promise for the treatment of mitochondrial dysfunction.

Topics: Cell Death; Cell Line, Tumor; Diterpenes; Drug Carriers; Gentamicins; Hair Cells, Auditory; Hearing Loss; Humans; Lysosomes; Mitochondria; Nanoparticles; Organophosphorus Compounds

Aminoglycoside-induced hearing loss stems from damage or loss of mechanosensory hair cells in the inner ear. Intrinsic mitochondrial cell death pathway plays a key role in that cellular dysfunction for which no proven effective therapies against oto-toxicities exist. Therefore, the aim of the present study was to develop a new mitochondrial targeting drug delivery system (DDS) that provided improved protection from gentamicin. Particularly, SS-31 peptide-conjugated geranylgeranylacetone (GGA) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles were constructed successfully via emulsion-solvent evaporation method. The zebrafish lateral line sensory system was used as an in vivo evaluating platform to investigate the protective efficiency against gentamicin. SS-31 modification significantly reduced the activity of mechanoelectrical transduction (MET) channel and gentamicin uptake in zebrafish lateral line hair cells. As expected, SS-31 conjugated nanoparticles showed mitochondrial specific accumulation in hair cells when compared with unconjugated formulations. Furthermore, intracellular SS-31 modified PLGA NPs slightly enhanced mitochondrial membrane potential (MMP, ΔΨ

Topics: Aminoglycosides; Animals; Cell Death; Diterpenes; Drug Delivery Systems; Ear, Inner; Gentamicins; Hair Cells, Auditory; Hearing Loss; Lactic Acid; Lateral Line System; Membrane Potential, Mitochondrial; Mitochondria; Nanoparticles; Oligopeptides; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Protective Agents; Zebrafish