Quantitative Evaluation of Cationic DOTAP-DOPC-DOPE Liposomal-Ceftriaxone Biodistribution and Ototoxicity for Targeted Trans-Tympanic Delivery in an Otitis Media Chinchilla Model

Introduction:: Otitis media, a common childhood affliction, poses treatment challenges due to the anatomical intricacies of the middle ear and the limitations of systemic oral antibiotics. Localized drug-delivery systems that target middle ear infections directly have the potential to significantly improve treatment strategies. This study quantitatively assesses the in vivo biodistribution and ototoxicity of cationic DOTAP-DOPC-DOPE liposomal-ceftriaxone (CFX) delivered via trans-tympanic administration for otitis media treatment in a chinchilla model.


Materials and Methods:: A cationic liposomal formulation featuring DOTAP, DOPC, and DOPE was optimized to load CFX, resulting in a hydrodynamic size of 121.5 ± 1.69 nm, a zeta potential of 21.1 ± 1.31 mV, and a loading capacity of 17.5 µg/mL. Adult male and female chinchillas were divided into groups (n=4 per group) and treated trans-tympanically with free CFX and liposomal-CFX, or a systemic oral control, twice daily for 3 or 10 days. Following treatment, animals were sacrificed, auditory bullae were excised, and middle ear (ME) cavities were lavaged with PBS to analyze drug delivery. Encapsulated CFX amounts in ME lavage fluid were determined using High-Performance Liquid Chromatography (HPLC) and UV absorbance at 270 nm wavelength.


Results, Conclusions, and Discussions:: Liposomal-CFX demonstrated a significant increase in drug delivery to the ME, with delivery rates enhanced as treatment duration escalated from 3 to 10 days. Free CFX administration exhibited minimal ME delivery, while very low serum uptake was observed, indicating an alternative absorption route other than trans-tympanic for free CFX. In contrast, 10-day oral treatment resulted in undetectable levels of CFX in the middle ear. These quantitative findings substantiate the hypothesis that cationic liposomes can efficaciously transport antibiotics across the intact tympanic membrane in a clinically relevant in vivo animal model.

The data presented corroborate the potential of cationic DOTAP-DOPC-DOPE liposomal-CFX for non-invasive trans-tympanic nanoparticle-antibiotic delivery in otitis media treatment. This optimized formulation facilitates effective drug delivery with minimal systemic exposure, off-target effects, and ototoxicity. This innovative approach offers a safe and efficacious solution for clinicians to treat otitis media without compromising patients' hearing and paves the way for the development of advanced drug delivery systems for other ear infection types.


Acknowledgements (Optional): :

References (Optional): :