Author:
Thomas Orasch (DE)
Abstract:
Background: The treatment options of life-threatening fungal infections are limited and need urgent improvement. The discovery of novelPolymeric nanoparticles for the delivery of antifungal drugs into pathogenic fungi antifungal compounds with new mode of actions is often not the limiting factor, rather than the pharmacological properties of the compounds inhibiting the novel targets, like low water solubility, high toxicity, or low bioavailability. The use of nanocarriers can overcome these limitations, as the pharmacological characteristics of these formulations are dominated by the polymer and not by the substance itself. However, the mechanism, how polymeric nanoparticles (NPs) deliver encapsulated substances into pathogenic fungi was suggested to be either endocytosis or endocytosis independent uptake of the whole NP, but is not fully understood. The aim of the study was to investigate, how polymeric NPs interact with pathogenic fungi and which substances can be efficiently transported by these nanocarriers.
Methods: 4 different polymers labelled with 3 different covalently attached fluorescent dyes were used to prepare the NPs. In addition, 3 different fluorescent dyes were encapsulated to track the NP and the cargo simultaneously. The interaction of the fluorescently labelled NPs with the molds Aspergillus fumigatus, A. nidulans, and A. terreus, or the yeasts Cryptococcus neoformans and Candida albicans was investigated by confocal laser scanning microscopy. Furthermore, the antifungal effect of the low water-soluble drug Itraconazole and the SidA inhibitor Celastrol encapsulated in these NPs was tested following the EUCAST methodology.
Results: Irrespective of the applied conditions (such as pH value or salt concentration in the medium, polymers used, size of the NPs, incubation time up to 24h, culture medium used), none of the used NPs reached the fungal cytosol, but adhered to the fungal surface. In-depth characterization revealed that the NPs cross the fungal cell wall, but remain in invaginations of the cytoplasmic membrane. Nevertheless, encapsulating the fluorescent dye coumarin-6 or Itraconazole lead to an accumulation of the fluorescent dye in the fungal lumen or a lower minimal inhibitory concentration compared to the pristine drug, respectively. In addition, the encapsulation of the other substances, which lead to no delivery, pointed out certain properties of hydrophobic substances, which are important for efficient delivery into pathogenic fungi.
Conclusions: Although NPs are not internalized by human pathogenic fungi, they can be used to efficiently deliver hydrophobic substances into these microorganisms, which may be helpful in the development of novel antifungal drugs
Abstract Number: 85
Conference Year: 2024
Conference abstracts, posters & presentations
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Title
Author
Year
Number
Poster
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v
Tianyu Lianga, Nir Osherovb, Ruoyu Lia, Qiqi Wanga, Wei Chena, Zhe Wana, Wei Liua*
2024
n/a
-
v
Jillian Simard, MD,1 Christopher Melani, MD,2
Rahul Lakhotia, MD,1
Michail S. Lionakis, MD
ScD,*,3
Stefania Pittaluga, MD PhD,4
James D. Phelan, PhD,*,1 Jagan R. Muppidi, MD
PhD,*,1
Lydia L. Chou, CRNP,*,1
Matthias Holdhoff, MD PhD,*,5 Michael Glantz, MD PhD,*,6
John A. Butman, MD PhD,*,7 Andrea Nicole Lucas, RN,*,8
Seth M. Steinberg, PhD,*,9
Elaine
S. Jaffe, MD,4
Louis M. Staudt, MD PhD,1
Wyndham H. Wilson, MD PhD,1 Mark Roschewski, MD102020
n/a
-
v
Mark Roschewski, MD,1
Christopher Melani, MD,2
Rahul Lakhotia, MD,3
Stefania Pittaluga, MD
PhD,4
James D. Phelan, PhD,*,3
Cody Peer, PhD,*,5 Michail S. Lionakis, MD ScD,*,6 Lydia
L. Chou, CRNP,*,3 Matthias Holdhoff, MD PhD,*,7 Michael Glantz, MD PhD,*,8 Jan Drappatz, MD,*,9
Catherine Lai, MD MPH,10 John A. Butman, MD PhD,*,11 Andrea Nicole Lucas, RN,*,12 Seth
M. Steinberg, PhD,*,13 William D. Figg, PhD,*,14 Elaine S. Jaffe, MD,4
S. Percy Ivy, MD,*,15
Richard F. Little, MDMPH,16 Louis M. Staudt, MD PhD,3
Wyndham H. Wilson, MD PhD32020
n/a
-
v
Binav Baral, MD,*,1 Prasanth Lingamaneni,*,2 Trilok Shrivastava, MD,*,3 Maryam Zia,4 Ishaan Vohra, MD,*,2
Krishna Rekha Moturi*,32020
903
n/a
-
v
Maxwell Green1, Scout Treadwell1, Geetha Gowda1, John Carlson, MD, PhD2
2023
610
n/a
-
v
Catherine Blackwood, PhD1 , Angela Lemons, MS2 , Rachael Rush3 , Walter McKinney2 , Dori Germolec4 , Donald Beezhold, PhD2 , Brett Green, PhD5 , Tara Croston, PhD6
2023
583
n/a
-
v
Catherine Blackwood, PhD1 , Angela Lemons, MS2 , Rachael Rush3 , Walter McKinney2 , Dori Germolec4 , Donald Beezhold, PhD2 , Brett Green, PhD5 , Tara Croston, PhD6
2023
583
n/a
-
v
Jennifer Roper, MD1, Sebastian Ochoa, MD2, Anahita
Agharahimi, MSN, CRNP2, Justina Pfister, RN2, Magdalena
Walkiewicz, PhD2, Amanda Urban, DNP, CRNP3, Rajarshi
Ghosh, PhD2, Michail Lionakis, MD, ScD2, Lisa Kohn, MD, PhD4, Kenneth Olivier, MD, MPH2, Alexandra Freeman, MD22023
516
n/a
-
v
Utkucan Acar, Gloria Sheng, Terrie Ahn, Lisa Kohn, Maria Garcia Lloret, Manish Butte
2022
82
n/a
-
v
C Gutierrez Perez1*, S Dhingra1,2, SM Kwansy3, TJ Opperman3, RA Cramer1
2022
93