Polyenes in Medium Chain Length Polyhydroxyalkanoate (mcl-PHA) Biopolymer Microspheres with Reduced Toxicity and Improved Therapeutic Effect Against Infection in Zebrafish Model

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2022 Apr 23

PMID 35456530

Authors

Aleksandar Pavic

Zoran Stojanovic

Marina Pekmezovic

dorde Veljovic

Kevin OConnor

Ivana Malagurski

Jasmina Nikodinovic-Runic

Affiliations

Soon will be listed here.

Abstract

Immobilizing antifungal polyenes such as nystatin (Nys) and amphotericin B (AmB) into biodegradable formulations is advantageous compared to free drug administration providing sustained release, reduced dosing due to localized targeting and overall reduced systemic drug toxicity. In this study, we encapsulated Nys and AmB in medium chain length polyhydroxyalkanoates (mcl-PHA) microspheres (7-8 µm in diameter). The obtained formulations have been validated for antifungal activity in vitro against a panel of pathogenic fungi including species of , , and genera and toxicity and efficacy in vivo using the zebrafish model of disseminated candidiasis. While free polyenes, especially AmB, were highly toxic to zebrafish embryos at the effective (MIC) doses, after their loading into mcl-PHA microspheres, inner organ toxicity and teratogenicity associated with both drugs were not observed, even at 100 × MIC doses. The obtained mcl-PHA/polyene formulations have successfully eradicated infection and showed an improved therapeutic profile in zebrafish by enhancing infected embryos survival. This approach is contributing to the antifungal arsenal as polyenes, although the first broad-spectrum antifungals on the market are still the gold standard for treatment of fungal infections.

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References

Cassar S, Adatto I, Freeman J, Gamse J, Iturria I, Lawrence C . Use of Zebrafish in Drug Discovery Toxicology. Chem Res Toxicol. 2019; 33(1):95-118. PMC: 7162671. DOI: 10.1021/acs.chemrestox.9b00335. View

Moen M, Lyseng-Williamson K, Scott L . Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs. 2009; 69(3):361-92. DOI: 10.2165/00003495-200969030-00010. View

Nasiri Sovari S, Radakovic N, Roch P, Crochet A, Pavic A, Zobi F . Combatting AMR: A molecular approach to the discovery of potent and non-toxic rhenium complexes active against C. albicans-MRSA co-infection. Eur J Med Chem. 2021; 226:113858. DOI: 10.1016/j.ejmech.2021.113858. View

Tverdek F, Kofteridis D, Kontoyiannis D . Antifungal agents and liver toxicity: a complex interaction. Expert Rev Anti Infect Ther. 2016; 14(8):765-76. DOI: 10.1080/14787210.2016.1199272. View

Lowery M, Greenberger P . Amphotericin-induced stridor: a review of stridor, amphotericin preparations, and their immunoregulatory effects. Ann Allergy Asthma Immunol. 2003; 91(5):460-6. DOI: 10.1016/S1081-1206(10)61514-1. View

MacRae C, Peterson R . Zebrafish as tools for drug discovery. Nat Rev Drug Discov. 2015; 14(10):721-31. DOI: 10.1038/nrd4627. View

Howell A, Isaacs D, Halliday R . Oral nystatin prophylaxis and neonatal fungal infections. Arch Dis Child Fetal Neonatal Ed. 2009; 94(6):F429-33. DOI: 10.1136/adc.2008.157123. View

Kahlmeter G, Brown D, Goldstein F, MacGowan A, Mouton J, Odenholt I . European Committee on Antimicrobial Susceptibility Testing (EUCAST) Technical Notes on antimicrobial susceptibility testing. Clin Microbiol Infect. 2006; 12(6):501-3. DOI: 10.1111/j.1469-0691.2006.01454.x. View

Cavassin F, Bau-Carneiro J, Vilas-Boas R, Queiroz-Telles F . Sixty years of Amphotericin B: An Overview of the Main Antifungal Agent Used to Treat Invasive Fungal Infections. Infect Dis Ther. 2021; 10(1):115-147. PMC: 7954977. DOI: 10.1007/s40121-020-00382-7. View

10.

Fradin C, de Groot P, MacCallum D, Schaller M, Klis F, Odds F . Granulocytes govern the transcriptional response, morphology and proliferation of Candida albicans in human blood. Mol Microbiol. 2005; 56(2):397-415. DOI: 10.1111/j.1365-2958.2005.04557.x. View

11.

Francis L, Meng D, Knowles J, Keshavarz T, Boccaccini A, Roy I . Controlled delivery of gentamicin using poly(3-hydroxybutyrate) microspheres. Int J Mol Sci. 2011; 12(7):4294-314. PMC: 3155352. DOI: 10.3390/ijms12074294. View

12.

Larranaga A, Fernandez J, Vega A, Etxeberria A, Ronchel C, Adrio J . Crystallization and its effect on the mechanical properties of a medium chain length polyhydroxyalkanoate. J Mech Behav Biomed Mater. 2014; 39:87-94. DOI: 10.1016/j.jmbbm.2014.07.020. View

13.

He J, Guo S, Zhu F, Zhu J, Chen Y, Huang C . A zebrafish phenotypic assay for assessing drug-induced hepatotoxicity. J Pharmacol Toxicol Methods. 2012; 67(1):25-32. DOI: 10.1016/j.vascn.2012.10.003. View

14.

Coelho J, Ferreira P, Alves P, Cordeiro R, Fonseca A, Gois J . Drug delivery systems: Advanced technologies potentially applicable in personalized treatments. EPMA J. 2012; 1(1):164-209. PMC: 3405312. DOI: 10.1007/s13167-010-0001-x. View

15.

Murueva A, Shishatskaya E, Kuzmina A, Volova T, Sinskey A . Microparticles prepared from biodegradable polyhydroxyalkanoates as matrix for encapsulation of cytostatic drug. J Mater Sci Mater Med. 2013; 24(8):1905-15. DOI: 10.1007/s10856-013-4941-2. View

16.

Hargreaves P, Nguyen T, Ryan R . Spectroscopic studies of amphotericin B solubilized in nanoscale bilayer membranes. Biochim Biophys Acta. 2006; 1758(1):38-44. DOI: 10.1016/j.bbamem.2006.01.001. View

17.

Pfaller M, Messer S, Moet G, Jones R, Castanheira M . Candida bloodstream infections: comparison of species distribution and resistance to echinocandin and azole antifungal agents in Intensive Care Unit (ICU) and non-ICU settings in the SENTRY Antimicrobial Surveillance Program (2008-2009). Int J Antimicrob Agents. 2011; 38(1):65-9. DOI: 10.1016/j.ijantimicag.2011.02.016. View

18.

Zhang Y, Han L, He Q, Chen W, Sun C, Wang X . A rapid assessment for predicting drug-induced hepatotoxicity using zebrafish. J Pharmacol Toxicol Methods. 2016; 84:102-110. DOI: 10.1016/j.vascn.2016.12.002. View

19.

Czeizel A, Kazy Z, Puho E . A population-based case-control teratological study of oral nystatin treatment during pregnancy. Scand J Infect Dis. 2004; 35(11-12):830-5. DOI: 10.1080/00365540310017069. View

20.

Weigt S, Huebler N, Strecker R, Braunbeck T, Broschard T . Developmental effects of coumarin and the anticoagulant coumarin derivative warfarin on zebrafish (Danio rerio) embryos. Reprod Toxicol. 2011; 33(2):133-41. DOI: 10.1016/j.reprotox.2011.07.001. View