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International audience; 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.

In this study, poly( e -caprolactone)-co-poly(ethylene glycol) copolymers grafted with a cationic ligand, propargyltrimethyl ammonium iodide (PTA), to fabricate the cationized triblock (P(CatCLCL) 2 -PEG) and diblock (P(CatCLCL)-mPEG) copolymers were investigated their potential use for oral delivery of enoxaparin (ENX). Influences of various PTA contents and different structures of the copolymers on molecular characteristics, ENX encapsulation, particle characteristics, and capability of drug transport across Caco-2 cells were elucidated. The results showed that P(CatCLCL) 2 -PEG and P(CatCLCL)-mPEG copolymers self-aggregated and encapsulated ENX into spherical particles of ∼200–450 nm. The increasing amount of PTA on the copolymers increased encapsulation efficiency of over 90%. The ENX release from both types of the cationized copolymer particles was pH-dependent which was retarded at pH 1.2 and accelerated at pH 7.4, supporting the drug protection in the acidic environment and possible release in the blood circulation. The toxicity of ENX-loaded particles on Caco-2 cells decreased when decreasing the amount of PTA. The triblock and diblock particles dramatically enhanced ENX uptake and transport across Caco-2 cells as compared to the ENX solution. However, the different structures of the copolymers slightly affected ENX transport. These results suggested that P(CatCLCL) 2 -PEG and P(CatCLCL)-mPEG copolymers would be potential carriers for oral delivery of ENX. Statement of Significance The anionic drugs such as proteins, peptides or polysaccharides are generally administered via invasive route causing patient incompliance and high cost of hospitalization. The development of biomaterials for non-invasive delivery of those drugs has gained much attention, especially for oral delivery. However, they have limitation due to non-biocompatibility and poor drug bioavailability. In this study, the novel poly( e -caprolactone)-co-poly(ethylene glycol) copolymers grafted with propargyltrimethyl ammonium iodide, a small cationic ligand, were introduced to use as a carrier for oral delivery of enoxaparin, a highly negatively charged drug. The study showed that these cationized copolymers could achieve high enoxaparin entrapment efficiency, protect drug release in an acidic environment and enhance enoxaparin permeability across Caco-2 cells, the intestinal cell model. These characteristics of the cationized copolymers make them a potential candidate for oral delivery of anionic drugs for biomaterial applications.