Local delivery polymer provides sustained antifungal activity of amphotericin B with reduced cytotoxicity

Abstract

A diverse range of clinical infections are on the increase, resulting in part from disruption of the natural microbiome, or even mycobiome, as a result of many different medical interventions. Amphotericin B (AmB) is a leading drug for the treatment of clinical fungal infections. However, AmB is extremely cytotoxic to mammalian cells, making use of the drug problematic. In this work, a drug delivery system made of polymerized cyclodextrin (pCD) allows for the localized administration of AmB, reducing the toxicity to host cells while retaining antifungal activity. A slow, sustained delivery rate of AmB was achieved through exploiting molecular interactions between the CD pockets and the drug. Surface plasmon resonance (SPR) and Fourier transform infrared spectroscopy (FTIR) were used to characterize the interaction between AmB and cyclodextrins (CDs). Through these methods, it was found that amphotericin binds strongly ([Formula: see text]M−1) to β-cyclodextrin. Release studies showed slow, sustained release of AmB from pCD disks. Antifungal activity was tested against Saccharomyces cerevisiae in assays for zone of inhibition, contact killing, and solution killing. In all assays, AmB-loaded pCD disks were found to exhibit significant antifungal activity. These results indicate that AmB-loaded pCD disks are capable of both the prevention of fungal growth and the elimination of established colonies. Additionally, results suggest that AmB exhibits antifungal activity whether associated with or released from pCD. The usage of pCD as a delivery vehicle also significantly reduces the toxic side effects of AmB, as seen in mammalian cell culture studies. These results show that in addition to reducing side-effects from systemic dosing, local delivery of AmB from pCD disks has the potential to improve its usage both in antifungal efficacy and reduced mammalian cell toxicity. Impact statement Amphotericin B (AmB) is an effective and commonly used antifungal agent. However, nephrotoxicity and poor solubility limits its usage. The proposed polymerized cyclodextrin (pCD) system therefore is an attractive method for AmB delivery, as it retains the antifungal activity of AmB while decreasing toxicity, and confining drug release to the local environment. This system could potentially be used for both prevention and treatment of established fungal infections, as AmB is toxic to fungus whether associated or released from pCD.

Affinity-Based Polymers Provide Long-Term Immunotherapeutic Drug Delivery Across Particle Size Ranges Optimal for Macrophage Targeting

“…LND also has poor solubility, increasing the difficulty of successfully delivering it to the area of treatment. In previous work, we have leveraged polymerized CDs (pCD) to continuously deliver hydrophobic, small molecule drugs on the order of weeks to months by leveraging affinity interactions [10][11][12][13][14][15][16][17][18][19][20][21] . A high concentration of affinity complexation sites to delay drug release is achieved by polymerizing CD monomers into larger disk structures, coatings, and more [11][12][13][22][23][24][25][26] .…”

Research Progress on Synthesis and Application of Cyclodextrin Polymers

“…The results indicate that when administered locally via FBG loaded with oCD-NH 2 /Dox, the therapeutic index of Dox may increase, providing the possibility for using these delivery systems to treat neuroblastoma. Haley et al [ 131 ] reported that a drug delivery system made of pCDs allowed for local administration of amphotericin B (AmB) (the leading drug for the treatment of clinical fungal infections), which can reduce toxicity to the host cells while maintaining the ability to eliminate fungal activity. By exploiting the molecular interaction between the CD cavity and the drug, a slow and sustained delivery rate of AmB was achieved.…”

Antifungal polymers for medical applications

“…Also, CS-dextran sulphate nanoparticles have been used for AmB loading (Tiyaboonchai & Limpeanchob, 2007). Another study used polycyclodextrins and dextran to keep AmB in the microscale with antifungal activity against the common yeast Saccharomyces cerevisiae (Haley et al, 2019).…”