Self-assembled Micelles Loaded with Itraconazole As Anti-Acanthamoeba Nano-formulation

Overview

Journal Arch Microbiol

Specialty Microbiology

Date 2024 Mar 3

PMID 38433145

Authors

Komal Rao

Muhammad Abdullah

Usman Ahmed

Hashi Isse Wehelie

Muhammad Raza Shah

Ruqaiyyah Siddiqui

Naveed A Khan

Bader S Alawfi

Ayaz Anwar

Affiliations

Soon will be listed here.

Abstract

Acanthamoeba castellanii are opportunistic pathogens known to cause infection of the central nervous system termed: granulomatous amoebic encephalitis, that mostly effects immunocompromised individuals, and a sight threatening keratitis, known as Acanthamoeba keratitis, which mostly affects contact lens wearers. The current treatment available is problematic, and is toxic. Herein, an amphiphilic star polymer with AB miktoarms [A = hydrophobic poly(ℇ-Caprolacton) and B = hydrophilic poly (ethylene glycol)] was synthesized by ring opening polymerization and Cu catalyzed azide-alkyne cycloaddition. Characterization by H and C NMR spectroscopy, size-exclusion chromatography and fluorescence spectroscopy was accomplished. The hydrophobic drug itraconazole (ITZ) was incorporated in self-assembled micellar structure of AB miktoarms through co-solvent evaporation. The properties of ITZ loaded (ITZ-PCL-PEG) and blank micelles (PCL-PEG) were investigated through zeta sizer, scanning electron microscopy and Fourier-transform infrared spectroscopy. Itraconazole alone (ITZ), polymer (DPB-PCL), empty polymeric micelles (PCL-PEG) alone, and itraconazole loaded in polymeric micelles (ITZ-PCL-PEG) were tested for anti-amoebic potential against Acanthamoeba, and the cytotoxicity on human cells were determined. The polymer was able to self-assemble in aqueous conditions and exhibited low value for critical micelle concentration (CMC) 0.05-0.06 µg/mL. The maximum entrapment efficiency of ITZ was 68%. Of note, ITZ, DPB, PCL-PEG and ITZ-PCL-PEG inhibited amoebae trophozoites by 37.34%, 36.30%, 35.77%, and 68.24%, respectively, as compared to controls. Moreover, ITZ-PCL-PEG revealed limited cytotoxicity against human keratinocyte cells. These results are indicative that ITZ-PCL-PEG micelle show significantly better anti-amoebic effects as compared to ITZ alone and thus should be investigated further in vivo to determine its clinical potential.

References

Abjani F, Khan N, Yousuf F, Siddiqui R . Targeting cyst wall is an effective strategy in improving the efficacy of marketed contact lens disinfecting solutions against Acanthamoeba castellanii cysts. Cont Lens Anterior Eye. 2015; 39(3):239-43. DOI: 10.1016/j.clae.2015.11.004. View

Ahmed U, Anwar A, Ong S, Anwar A, Khan N . Applications of medicinal chemistry for drug discovery against Acanthamoeba infections. Med Res Rev. 2021; 42(1):462-512. DOI: 10.1002/med.21851. View

Ahmed U, Ho K, Eugin Simon S, Saad S, Ong S, Anwar A . Potential anti-acanthamoebic effects through inhibition of CYP51 by novel quinazolinones. Acta Trop. 2022; 231:106440. DOI: 10.1016/j.actatropica.2022.106440. View

Ahmed U, Manzoor M, Qureshi S, Mazhar M, Fatima A, Aurangzeb S . Anti-amoebic effects of synthetic acridine-9(10H)-one against brain-eating amoebae. Acta Trop. 2023; 239:106824. DOI: 10.1016/j.actatropica.2023.106824. View

Alcazar-Fuoli L, Mellado E . Ergosterol biosynthesis in Aspergillus fumigatus: its relevance as an antifungal target and role in antifungal drug resistance. Front Microbiol. 2013; 3:439. PMC: 3541703. DOI: 10.3389/fmicb.2012.00439. View

Anwar A, Mungroo M, Khan S, Fatima I, Rafique R, Kanwal . Novel Azoles as Antiparasitic Remedies against Brain-Eating Amoebae. Antibiotics (Basel). 2020; 9(4). PMC: 7235764. DOI: 10.3390/antibiotics9040188. View

Boehm H, Boehringer M, Bur D, Gmuender H, Huber W, Klaus W . Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening. J Med Chem. 2000; 43(14):2664-74. DOI: 10.1021/jm000017s. View

Croy S, Kwon G . Polymeric micelles for drug delivery. Curr Pharm Des. 2006; 12(36):4669-84. DOI: 10.2174/138161206779026245. View

DeCato S, Bemis T, Madsen E, Mecozzi S . Synthesis and characterization of perfluoro--butyl semifluorinated amphiphilic polymers and their potential application in hydrophobic drug delivery. Polym Chem. 2014; 5(22):6461-6471. PMC: 4217224. DOI: 10.1039/C4PY00882K. View

10.

Gazdar A, Minna J . Targeted therapies for killing tumor cells. Proc Natl Acad Sci U S A. 2001; 98(18):10028-30. PMC: 56907. DOI: 10.1073/pnas.191379998. View

11.

Gerpe A, Aguirre G, Boiani L, Cerecetto H, Gonzalez M, Olea-Azar C . Indazole N-oxide derivatives as antiprotozoal agents: synthesis, biological evaluation and mechanism of action studies. Bioorg Med Chem. 2006; 14(10):3467-80. DOI: 10.1016/j.bmc.2006.01.007. View

12.

Habib S, Jawad-Ur-Rehman , Maharjan R, Kanwal T, Althagafi I, Saifullah S . Synthesis of lactobionic acid based bola-amphiphiles and its application as nano-carrier for curcumin delivery to cancer cell cultures in-vitro. Int J Pharm. 2020; 590:119897. DOI: 10.1016/j.ijpharm.2020.119897. View

13.

Hernandez-Martinez D, Reyes-Batlle M, Castelan-Ramirez I, Hernandez-Olmos P, Vanzzini-Zago V, Ramirez-Flores E . Evaluation of the sensitivity to chlorhexidine, voriconazole and itraconazole of T4 genotype Acanthamoeba isolated from Mexico. Exp Parasitol. 2019; 197:29-35. DOI: 10.1016/j.exppara.2019.01.006. View

14.

Iha R, Wooley K, Nystrom A, Burke D, Kade M, Hawker C . Applications of orthogonal "click" chemistries in the synthesis of functional soft materials. Chem Rev. 2009; 109(11):5620-86. PMC: 3165017. DOI: 10.1021/cr900138t. View

15.

Jeyamogan S, Khan N, Anwar A, Raza Shah M, Siddiqui R . Cytotoxic effects of Benzodioxane, Naphthalene diimide, Porphyrin and Acetamol derivatives on HeLa cells. SAGE Open Med. 2018; 6:2050312118781962. PMC: 6048657. DOI: 10.1177/2050312118781962. View

16.

Kalra S, Sharma P, Shyam K, Tejan N, Ghoshal U . Acanthamoeba and its pathogenic role in granulomatous amebic encephalitis. Exp Parasitol. 2019; 208:107788. DOI: 10.1016/j.exppara.2019.107788. View

17.

Kumar V, Wang L, Riebe M, Tung H, Prudhomme R . Formulation and stability of itraconazole and odanacatib nanoparticles: governing physical parameters. Mol Pharm. 2009; 6(4):1118-24. DOI: 10.1021/mp900002t. View

18.

Lamb D, Warrilow A, Rolley N, Parker J, Nes W, Smith S . Azole Antifungal Agents To Treat the Human Pathogens Acanthamoeba castellanii and Acanthamoeba polyphaga through Inhibition of Sterol 14α-Demethylase (CYP51). Antimicrob Agents Chemother. 2015; 59(8):4707-13. PMC: 4505289. DOI: 10.1128/AAC.00476-15. View

19.

Lotocki V, Kakkar A . Miktoarm Star Polymers: Branched Architectures in Drug Delivery. Pharmaceutics. 2020; 12(9). PMC: 7559275. DOI: 10.3390/pharmaceutics12090827. View

20.

Maciver S, Asif M, Simmen M, Lorenzo-Morales J . A systematic analysis of Acanthamoeba genotype frequency correlated with source and pathogenicity: T4 is confirmed as a pathogen-rich genotype. Eur J Protistol. 2013; 49(2):217-21. DOI: 10.1016/j.ejop.2012.11.004. View