Nanoparticle-Mediated Delivery of Deferasirox: A Promising Strategy Against Invasive Aspergillosis

Overview

Journal Bioengineering (Basel)

Date 2024 Nov 27

PMID 39593775

Authors

Sydney Peppe

Moloud Farrokhi

Evan A Waite

Mustafa Muhi

Efthymia Iliana Matthaiou

Affiliations

Soon will be listed here.

Abstract

Background: Invasive aspergillosis (IA) is a deadly fungal lung infection. Antifungal resistance and treatment side effects are major concerns. Iron chelators are vital for IA management, but systemic use can cause side effects. We developed nanoparticles (NPs) to selectively deliver the iron chelator deferasirox (DFX) for IA treatment.

Methods: DFX was encapsulated in poly(lactic-co-glycolic acid) (PLGA) NPs using a single emulsion solvent evaporation method. The NPs were characterized by light scattering and electron microscopy. DFX loading efficiency and release were assessed spectrophotometrically. Toxicity was evaluated using SRB, luciferase, and XTT assays. Therapeutic efficacy was tested in an IA mouse model, assessing fungal burden by qPCR and biodistribution via imaging.

Results: DFX-NPs had a size of ~50 nm and a charge of ~-30 mV, with a loading efficiency of ~80%. Release kinetics showed DFX release via diffusion and bioerosion. The EC50 of DFX-NPs was significantly lower ( < 0.001) than the free drug, and they were significantly less toxic ( < 0.0001) in mammalian cell cultures. In vivo, NP treatment significantly reduced burden ( < 0.05).

Conclusion: The designed DFX-NPs effectively target and kill with minimal toxicity to mammalian cells. The significant in vivo therapeutic efficacy suggests these NPs could be a safe and effective treatment for IA.

References

Kumar A, Lunawat A, Kumar A, Sharma T, Islam M, Kahlon M . Recent Trends in Nanocarrier-Based Drug Delivery System for Prostate Cancer. AAPS PharmSciTech. 2024; 25(3):55. DOI: 10.1208/s12249-024-02765-2. View

Perez R, Godwin A, Handel L, Hamilton T . A comparison of clonogenic, microtetrazolium and sulforhodamine B assays for determination of cisplatin cytotoxicity in human ovarian carcinoma cell lines. Eur J Cancer. 1993; 29A(3):395-9. DOI: 10.1016/0959-8049(93)90394-u. View

Bairwa G, Jung W, Kronstad J . Iron acquisition in fungal pathogens of humans. Metallomics. 2017; 9(3):215-227. PMC: 5734051. DOI: 10.1039/c6mt00301j. View

Lu Y, Cheng D, Niu B, Wang X, Wu X, Wang A . Properties of Poly (Lactic-co-Glycolic Acid) and Progress of Poly (Lactic-co-Glycolic Acid)-Based Biodegradable Materials in Biomedical Research. Pharmaceuticals (Basel). 2023; 16(3). PMC: 10058621. DOI: 10.3390/ph16030454. View

Haas H . Iron - A Key Nexus in the Virulence of Aspergillus fumigatus. Front Microbiol. 2012; 3:28. PMC: 3272694. DOI: 10.3389/fmicb.2012.00028. View

Musumeci T, Ventura C, Giannone I, Ruozi B, Montenegro L, Pignatello R . PLA/PLGA nanoparticles for sustained release of docetaxel. Int J Pharm. 2006; 325(1-2):172-9. DOI: 10.1016/j.ijpharm.2006.06.023. View

Zhang W . Nanoparticle aggregation: principles and modeling. Adv Exp Med Biol. 2014; 811:19-43. DOI: 10.1007/978-94-017-8739-0_2. View

Kutscher H, Chao P, Deshmukh M, Singh Y, Hu P, Joseph L . Threshold size for optimal passive pulmonary targeting and retention of rigid microparticles in rats. J Control Release. 2010; 143(1):31-7. PMC: 2840186. DOI: 10.1016/j.jconrel.2009.12.019. View

Matthaiou E, Sass G, Stevens D, Hsu J . Iron: an essential nutrient for Aspergillus fumigatus and a fulcrum for pathogenesis. Curr Opin Infect Dis. 2018; 31(6):506-511. PMC: 6579532. DOI: 10.1097/QCO.0000000000000487. View

10.

Li S, Chen L, Fu Y . Nanotechnology-based ocular drug delivery systems: recent advances and future prospects. J Nanobiotechnology. 2023; 21(1):232. PMC: 10362606. DOI: 10.1186/s12951-023-01992-2. View

11.

Giddabasappa A, Gupta V, Norberg R, Gupta P, Spilker M, Wentland J . Biodistribution and Targeting of Anti-5T4 Antibody-Drug Conjugate Using Fluorescence Molecular Tomography. Mol Cancer Ther. 2016; 15(10):2530-2540. DOI: 10.1158/1535-7163.MCT-15-1012. View

12.

van Rhijn N, Bromley M . The Consequences of Our Changing Environment on Life Threatening and Debilitating Fungal Diseases in Humans. J Fungi (Basel). 2021; 7(5). PMC: 8151111. DOI: 10.3390/jof7050367. View

13.

Nikula K, Avila K, Griffith W, Mauderly J . Sites of particle retention and lung tissue responses to chronically inhaled diesel exhaust and coal dust in rats and cynomolgus monkeys. Environ Health Perspect. 1997; 105 Suppl 5:1231-4. PMC: 1470143. DOI: 10.1289/ehp.97105s51231. View

14.

Garanina A, Vishnevskiy D, Chernysheva A, Malinovskaya J, Lazareva P, Semkina A . The Internalization Pathways of Liposomes, PLGA, and Magnetic Nanoparticles in Neutrophils. Biomedicines. 2024; 12(10). PMC: 11505478. DOI: 10.3390/biomedicines12102180. View

15.

Denning D . Global incidence and mortality of severe fungal disease. Lancet Infect Dis. 2024; 24(7):e428-e438. DOI: 10.1016/S1473-3099(23)00692-8. View

16.

Cho Y, Yoon J, Song S, Noh Y . Mitochondrial DNA as a target for analyzing the biodistribution of cell therapy products. Sci Rep. 2024; 14(1):7934. PMC: 10995129. DOI: 10.1038/s41598-024-56591-4. View

17.

Gow N, Latge J, Munro C . The Fungal Cell Wall: Structure, Biosynthesis, and Function. Microbiol Spectr. 2017; 5(3). PMC: 11687499. DOI: 10.1128/microbiolspec.FUNK-0035-2016. View

18.

Vasquez K, Casavant C, Peterson J . Quantitative whole body biodistribution of fluorescent-labeled agents by non-invasive tomographic imaging. PLoS One. 2011; 6(6):e20594. PMC: 3120766. DOI: 10.1371/journal.pone.0020594. View

19.

Forest V, Pourchez J . Human biological monitoring of nanoparticles, a new way to investigate potential causal links between exposure to nanoparticles and lung diseases?. Pulmonology. 2022; 29(1):4-5. DOI: 10.1016/j.pulmoe.2022.08.005. View

20.

Korfanty G, Heifetz E, Xu J . Assessing thermal adaptation of a global sample of : Implications for climate change effects. Front Public Health. 2023; 11:1059238. PMC: 9978374. DOI: 10.3389/fpubh.2023.1059238. View