| Gentamicin (GM) is an aminoglycoside antibiotic used for treating many types of bacterial infections, particularly those caused by gram-negative bacteria. However, the side effects of GM, i.e. ototoxicity and nephrotoxicity, restrict its clinical application. A number of researches have suggested that the free radicals were involved in the ototoxicity of GM. In practice, GM is injected once daily while SA needs to be injected twice a day. The multiple injections bring inconvenience for the patients. In addition, once the free radicals generate, they will immediately react with the vicinal macromolecules due to their highly activity. In order to effectively inhibit the ototoxicity of the free radicals of GM, scavengers need to be available to react with the free radicals as soon as they are produced. Separating injections may result in poor coordination of GM and SA in vivo, and consequently reduce the antagonism of SA.CS nanoparticles have many advantages, such as the site-specific and controlled release delivery can improve the bioavailability of the drug and minimize their side effects. However, the poor water solubility of chitosan (only soluble in weak acidic solution) is one of main drawbacks for its application in drug delivery system. O-carboxymethyl chitosan (O-CMC) is a water soluble CS derivative, which has many outstanding properties including nontoxicity, biodegradability, biocompatibility, antibacterial activity and improvement of the retention time and antifungal bioactivity. Furthermore, the O-CMC nanoparticles could be synthesized via the cross-linking method between carboxyl (COOH) of O-CMC and calcium ion in neutral or weakly basic pH range, without the need of any acidic.In this paper, O-CMC nanoparticles and CS nanoparticles loading with GM and SA have been prepared and used to inhibit the ototoxicity of GM. The optimum conditions of SA/GM/CS nanoparticles were that the concentration of CS was 0.2% (w/v), the mass ratio of CS to cross-linking agent was 5:1, the pH of CS was 4.5, the feed ratio of SA to GM was 1.5:1.0, and the mass ratio of drug to polymer was 1:4. And the optimum conditions of SA/GM/O-CMC nanoparticles were that the concentration of O-CMC was 0.2% (w/v), the mass ratio of O-CMC to CaCl2 was 4.5:1.0, the pH of O-CMC was 7.2, the feed ratio of SA to GM was 1.5:1.0, and the added drug was 4mg.The SA/GM/CS nanoparticles and SA/GM/O-CMC nanoparticles were spherical in shape, and the average size was ranging from 200 nm to 400 nm by the observing of transmission electron microscope and scanning electron microscope.And the results of Fourier transform infrared spectrum and XRD spectrum indicated that some interaction between CS or O-CMC with cross-linking agents have occurred within the nanoparticles, and SA and GM have been successfully loaded into the nanoparticles.In the in vitro release study, the release rate was higher in the case of formulations containing higher amount of drugs, and similarly, drug release was lower for formulations having a lower amount of drugs. And when the feed ratio of SA to GM was 1.5:1.0, the amounts of SA and GM released from the nanoparticles met the dosage ratio requirement for inhibiting ototoxicity of GM by SA. And in the in vitro inhibit free radicals study, the hydroxyl radical clearance of SA/GM/O-CMC nanoparticles was higher than SA/GM/CS nanoparticles because of the high entrapment efficience of SA. And the oxygen radical clearance of O-CMC is related to the degree of substitution, and in this stud, the oxygen radical clearance of O-CMC nanoparticles was not higher than CS nanopaeticles. These results indicated that SA/GM/O-CMC nanoparticles had the potential effect of inhibiting the ototoxicity of SA. |
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