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Drug Delivery

Drug Delivery - Poster Session E

Poster X17 - Thermosensitive Antifungal Hydrogel for Nasal Delivery

Saturday, October 26, 2024
10:00 AM – 11:00 AM EST
Location: Exhibit Hall E, F & G

Introduction:  Invasive fungal infections, especially in the nasal cavity, are nothing short of a death sentence. Mucormycosis, also known as “black fungus,” possesses a mortality rate of ~54% and predominantly afflicts immunodeficient patients with diabetes, cancer, and autoimmune diseases. More than 80% of patients need invasive surgery immediately to excise infected tissues, and the high doses of intravenously administered antifungals often leads to renal failure. Current clinical methods of local administration of antifungals are inefficient and time-consuming, including gauze packing soaked with antifungals, local injection of liposomal solution, and a lavage of the affected tissue surface with the liposomal intravenous solution. This study introduces a novel thermosensitive hydrogel designed for localized delivery of amphotericin B (AmB) to the nasal mucosa and upper respiratory tract. This hydrogel is formulated with Pluronic F127 (PLF127) solubilized in surgical saline and enhanced with hyaluronic acid (HA) for improved mucoadhesion.

Materials and

Methods:  The rheological properties of formulations containing varying concentrations of PLF127, HA, and AmB were investigated to determine their sol-gel transition temperatures across a range from 15°C to 45°C. This characterization facilitated the identification of optimal conditions for thermosensitive behavior suitable for nasal application. Preliminary cytotoxicity assays involved drop-wise application of drug-loaded hydrogel onto cultured WI-38 fibroblasts. Morphological changes were monitored through periodic imaging at various time points, with cells stained for actin and nuclei. Dissolution characteristics of the hydrogel in cell media were observed in a 2:5 gel-to-media ratio until gels dissolved completely, to assess its potential for clearance from nasal passages with minimal obstruction.

Results, Conclusions, and Discussions: Initial studies demonstrated that formulations containing 15–20% Pluronic F127 (PLF127) loaded with amphotericin B (AmB) efficiently transitioned from liquid to semi-solid upon reaching 37℃. This thermosensitive behavior enables potential administration of the liquified hydrogel via spray or modified nasogastric tube, followed by solidification upon contact with the patient’s mucosa. Preliminary cytotoxicity assessments involved drop-wise application of the drug-loaded hydrogel onto cultured WI-38 fibroblasts. Direct contact with PLF127 adversely affected cell viability and morphology, resulting in thin yet still elongated cells with seemingly porous membranes only in the presence of AmB. However, these effects diminished distally, indicating reduced systemic exposure and toxicity. This reflected the predicted cytotoxicity of antifungals, which fail to distinguish between ergosterol, the primary sterol in fungal cell membranes, and cholesterol in mammalian cells due to their broad-spectrum action. Degradation tests show that the hydrogel completely dissolved in cell media within 3 hours in a 2:5 ratio of gel-to-media, suggesting potential for easy clearance from the nasal tract with minimal airway obstruction.
The results underscore the feasibility of using thermosensitive hydrogels for targeted delivery of antifungal agents to mucosal surfaces, highlighting advantages such as prolonged drug release and reduced systemic toxicity. Further optimization is warranted to enhance formulation stability and efficacy under physiological conditions, ensuring robust clinical translation. Future studies should focus on refining cytotoxicity assessments to better simulate dynamic cellular environments and validate these findings in relevant animal models.
Overall, this innovative approach represents a critical step towards advancing fungal infection treatment paradigms, potentially transforming clinical practice and patient care outcomes and reducing healthcare burdens associated with invasive fungal treatments.

Acknowledgements (Optional):  I would like to express gratitude to my mentor, Devon Hartigan, and the Sadtler lab for their invaluable support and feedback throughout this project. Special thanks to Vanathi Sundaresan for her expert guidance and assistance with cell culture techniques.