Injectable in situ cross-linking hydrogels for local antifungal therapy

Abstract

Invasive fungal infections can be devastating, particularly in immunocompromised patients, and difficult to treat with systemic drugs. Furthermore, systemic administration of those medications can have severe side effects. We have developed an injectable local antifungal treatment for direct administration into existing or potential sites of fungal infection. Amphotericin B (AmB), a hydrophobic, potent, and broad-spectrum antifungal agent, was rendered water-soluble by conjugation to a dextran-aldehyde polymer. The dextran-aldehyde-AmB conjugate retained antifungal efficacy against C. albicans. Mixing carboxymethylcellulose-hydrazide with dextran-aldehyde formed a gel that cross-linked in situ by formation of hydrazone bonds. The gel provided in vitro release of antifungal activity for 11 days, and contact with the gel killed Candida for three weeks. There was no apparent tissue toxicity in the murine peritoneum and the gel caused no adhesions. Gels produced by entrapment of a suspension of AmB in CMC-dextran without conjugation of drug to polymers did not release fungicidal activity, but did kill on contact. Injectable systems of these types, containing soluble or insoluble drug formulations, could be useful for treatment of local antifungal infections, with or without concurrent systemic therapy.

Designing Injectable, Covalently Cross‐Linked Hydrogels for Biomedical Applications

“…[ 173 ] Similarly, Kohane and co-workers reported the use of aldehydefunctionalized dextran and hydrazide-functionalized carboxymethylcellulose with an excess of aldehydes to generate injectable reservoirs for the prolonged release of hydrophobic anti-fungal therapeutics containing an amine group, which formed a Schiff base with the excess aldehyde groups. [ 174 ] The ready reversibility of this bond in water facilitated sustained release of the hydrophobic therapeutic.…”

Candida Biofilms: Environmental and Clinical Aspects

“…Hudson et al [34] describe a novel form of amphotericin B, dextran aldehyde conjugate with amphotericin B, preservative gel formulation used in local treatment of infections (ligaments, vascular catheters, bones) caused by Candida sp. bioilm.…”

Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine

“…In addition, pH and temperature dually responsive injectable hydrogels based on biocompatible glycol chitosan and thermo-sensitive benzaldehyde-capped Pluronic ® were reported [153]. In the approach using Schiff’s base reaction to form hydrogels, aldehydes of macromers can also react with some tissues and encapsulated payloads containing amine groups [154,155], which leads to delayed release or/and may alter hydrogel properties.…”

“…The same method was employed to conjugate amphotericin B (AmB), an antifungal agent, to aldehyde groups of DEX-CMC hydrogels (Fig. 9) [154]. The release rate was decreased when a higher degree of hydrogel crosslinking was employed.…”