Hybrid systems combining liposomes and entangled hyaluronic acid chains: Influence of liposome surface and drug encapsulation on the microstructure.

Mixtures of hyaluronic acid (HA) with liposomes lead to hybrid colloid-polymer systems with a great interest in drug delivery. However, little is known about their microstructure. Small angle neutron scattering (SANS) is a valuable tool to characterize these systems in the semi-dilute entangled regime (1.5% HA) at high liposome concentration (80 mM lipids). The objective was to elucidate the influence of liposome surface (neutral, cationic, anionic or anionic PEGylated), drug encapsulation and HA concentration in a buffer mimicking biological fluids (37 °C). First, liposomes were characterized by SANS, cryo-electron microscopy, and dynamic light scattering and HA by SANS, size exclusion chromatography, and rheology. Secondly, HA-liposome mixtures were studied by SANS. In HA, liposomes kept their integrity. Anionic and PEGylated liposomes were in close contact within dense clusters with an amorphous organization. The center-to-center distance between liposomes corresponded to twice their diameter. A depletion mechanism could explain these findings. Encapsulation of a corticoid did not modify this organization. Cationic liposomes formed less dense aggregates and were better dispersed due to their complexation with HA. Liposome surface governed the interactions and microstructure of these hybrid systems.

Transtympanic injection of a liposomal gel loaded with N-acetyl-L-cysteine: A relevant strategy to prevent damage induced by cochlear implantation in guinea pigs?

Patients with residual hearing can benefit from cochlear implantation. However, insertion can damage cochlear structures and generate oxidative stress harmful to auditory cells. The antioxidant N-acetyl-L-cysteine (NAC) is a precursor of glutathione (GSH), a powerful endogenous antioxidant. NAC local delivery to the inner ear appeared promising to prevent damage after cochlear implantation in animals. NAC-loaded liposomal gel was specifically designed for transtympanic injection, performed both 3 days before and on the day of surgery. Hearing thresholds were recorded over 30 days in implanted guinea pigs with and without NAC. NAC, GSH, and their degradation products, N,N'-diacetyl-L-cystine (DiNAC) and oxidized glutathione (GSSG) were simultaneously quantified in the perilymph over 15 days in non-implanted guinea pigs. For the first time, endogenous concentrations of GSH and GSSG were determined in the perilymph. Although NAC-loaded liposomal gel sustained NAC release in the perilymph over 15 days, it induced hearing loss in both implanted and non-implanted groups with no perilymphatic GSH increase. Under physiological conditions, NAC appeared poorly stable within liposomes. As DiNAC was quantified at concentrations which were twice as high as NAC in the perilymph, it was hypothesized that DiNAC could be responsible for the adverse effects on hearing.

Nanocarriers for drug delivery to the inner ear: Physicochemical key parameters, biodistribution, safety and efficacy.

Despite the high incidence of inner ear disorders, there are still no dedicated medications on the market. Drugs are currently administered by the intratympanic route, the safest way to maximize drug concentration in the inner ear. Nevertheless, therapeutic doses are ensured for only a few minutes/hours using drug solutions or suspensions. The passage through the middle ear barrier strongly depends on drug physicochemical characteristics. For the past 15 years, drug encapsulation into nanocarriers has been developed to overcome this drawback. Nanocarriers are well known to sustain drug release and protect it from degradation. In this review, in vivo studies are detailed concerning nanocarrier biodistribution, their pathway mechanisms in the inner ear and the resulting drug pharmacokinetics. Key parameters influencing nanocarrier biodistribution are identified and discussed: nanocarrier size, concentration, surface composition and shape. Recent advanced strategies that combine nanocarriers with hydrogels, specific tissue targeting or modification of the round window permeability (cell-penetrating peptide, magnetic delivery) are explored. Most of the nanocarriers appear to be safe for the inner ear and provide a significant efficacy over classic formulations in animal models. However, many challenges remain to be overcome for future clinical applications.