Approaches for Targeting Naegleria fowleri Using Nanoparticles and Artificial Peptides
Abstract
:1. Introduction
2. Challenges in Crossing the Blood–Brain Barrier (BBB)
3. Naegleria fowleri: Pathogenesis and Diagnosis
4. Current Treatment Protocols
5. Recent Research on Trophocidal Compounds
5.1. Potentially Crossing BBB
5.2. Sterol Biosynthesis Inhibitors
5.3. Nanomaterials Demonstrating Efficacy In Vitro
5.3.1. Silver
AmB and Nystatin Conjugated to Silver Nanoparticles
Flavonoid-Conjugated Nanoparticles Stabilized by Plant Gums
Guanabenz Silver- and Gold-Conjugated Nanoparticles
5.3.2. Gold
Trans-Cinnamic Acid-Conjugated Gold Nanoparticles (CA-AuNPs)
Curcumin-Conjugated Gold Nanoparticles
5.3.3. Other Nanomaterial Conjugates
Polyaniline-Hexagonal Boron Nitride (PANI/hBN)
Polyaniline: Tungsten Disulfide (PANI:WS2) Nanoparticles
Compounds | Average Diameter of Nanomaterials (nm) 1 | Result of In Vitro Studies 2 | Reference |
---|---|---|---|
AmB-AgNPs | 10–90 | Trophozoites were treated with compounds at 2.5 μM for 24 h. AmB-AgNP-treated trophozoites saw amoeba viability reduced to 22% compared to AmB-only treated trophozoites at 40% viability. | [36] |
Nystatin-AgNPs | 10–90 | Trophozoites were treated with compounds at 2.5 μM. Nystatin alone reduced trophozoite viability to 82% compared to nystatin-AgNPs, which further reduced cell viability to 63%. | [36] |
GA-AgNPs-HDN | 182.8 | Trophozoites were incubated with compounds at 25 μg/mL. | [37] |
GA-AgNPs-HDN reduced trophozoite viability by 99% and was more effective than cell treatment with AmB alone. | |||
GNB-AgNPs GNB-AuNPs | 50–150 50–70 | Trophozoites were incubated with compounds at 2.5 and 5 μM. The amoebicidal activity of the GNB-conjugated nanoconjugates was compared against trophozoites treated with 100 μM of AmB. GNB alone only displayed anti-amoebic activity at 50 and 100 μM, whereas the GNB-conjugated nanoconjugates displayed high potency as low as 2.5 μM. | [40] |
CA-AuNPs | 89 | Trophozoites were treated with varying concentrations of compounds, and the amoebicidal activity was compared to 50 μM AmB. Treatment with 50 μM AmB reduced trophozoite viability from approximately 9.5 × 105 to 1.6 × 105, which is comparable to the anti-amoebic effect shown for the CA-AuNPs. | [44] |
Curcumin-AuNPs | 53 | Trophozoites were treated with varying concentrations of compounds. Amoebicidal activity was compared against miltefosine. At 200 μM, curcumin alone displayed 66% amoebicidal activity against N. fowleri trophozoites, and the IC50 was determined to be 74 μM. Comparatively, 10 μM of curcumin-AuNPs displayed 69% amoebicidal activity. AuNP alone showed insignificant amoebicidal activity. | [45] |
PANI/hBN | N.D. | Trophozoites were treated with 100 μg/mL of PANI/hBN nanocomposite ratios of 1:1, 1:2, and 1:5. Amoebicidal activity was compared against miltefosine. Treatment with 1:5 PANI/hBN reduced cell viability by 58%. The 1:1 and 1:2 PANI/hBN treatments only inhibited trophozoite growth by 50% and 40%, respectively. The individual components were less effective at reducing trophozoite viability. | [46] |
PANI-WS2 | N.D. | Trophozoites were treated with 100 μg/mL of 1:1, 1:2, and 1:5 PANI-WS2 nanocomposites. Amoebicidal activity was compared against miltefosine. The 1:5 PANI-WS2 nanocomposite was the most effective at reducing trophozoite viability, by 54%, followed by 1:2 with 36% and 1:1 with 20%. WS2 and PANI alone were less effective at reducing cell viability. | [49] |
5.4. Shuttle Peptide
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Marciano-Cabral, F.; Cabral, G.A. The immune response to Naegleria fowleri amebae and pathogenesis of infection. FEMS Immunol. Med. Microbiol. 2007, 51, 243–259. [Google Scholar] [CrossRef]
- Güémez, A.; García, E. Primary Amoebic Meningoencephalitis by Naegleria fowleri: Pathogenesis and Treatments. Biomolecules 2021, 11, 1320. [Google Scholar] [CrossRef]
- Grace, E.; Asbill, S.; Virga, K. Naegleria fowleri: Pathogenesis: Diagnosis, and Treatment Options. Antimicrob. Agents Chemother. 2015, 59, 6677–6681. [Google Scholar] [CrossRef] [PubMed]
- Baig, A.M. Primary Amoebic Meningoencephalitis: Neurocehmotaxis and Neurotropic Preferences of Naegleria fowleri. ACS Chem. Neurosci. 2016, 7, 1026–1029. [Google Scholar] [CrossRef]
- Illness and Symptoms|Naegleria fowleri|CDC. Available online: https://www.cdc.gov/parasites/naegleria/illness.html (accessed on 16 January 2024).
- Lombardo, S.M.; Schneider, M.; Türeli, A.E.; Günday Türeli, N. Key for crossing the BBB with nanoparticles: The rational design. Beilstein J. Nanotechnol. 2020, 11, 866–883. [Google Scholar] [CrossRef] [PubMed]
- Wu, D.; Chen, Q.; Chen, X.; Han, F.; Chen, Z.; Wang, Y. The Blood-Brain Barrier: Structure, Regulation, and Drug Delivery. Signal Transduct. Target. Ther. 2023, 8, 217. [Google Scholar] [CrossRef]
- Terstappen, G.C.; Meyer, A.H.; Bell, R.D.; Zhang, W. Strategies for Delivering Therapeutics across the Blood-Brain Barrier. Nat. Rev. Drug Discov. 2021, 20, 362–383. [Google Scholar] [CrossRef] [PubMed]
- Martínez-Castillo, M.; Cárdenas-Zúñiga, R.; Coronado-Velázquez, D.; Debnath, A.; Serrano-Luna, J.; Shibayama, M. Naegleria fowleri after 50 years: Is it a neglected pathogen? J. Med. Microbiol. 2016, 65, 885–896. [Google Scholar] [CrossRef]
- Martinez, A.J. Free-Living Amebas: Natural History, Prevention, Diagnosis, Pathology, and Treatment of Disease; CRC Press Inc.: Boca Raton, FL, USA, 1985. [Google Scholar]
- Visvesvara, G.S.; Moura, H.; Schuster, F.L. Pathogenic and Opportunistic Free-Living Amoebae: Acanthamoeba spp.; Balamuthia mandrillaris, Naegleria fowleri, and Sappinia diploidea. FEMS Immunol. Med. Microbiol. 2007, 50, 1–26. [Google Scholar] [CrossRef]
- Treatment|Naegleria fowleri|CDC. Available online: https://www.cdc.gov/parasites/naegleria/treatment-hcp.html (accessed on 30 January 2024).
- Schuster, F.L.; Rechthand, E. In Vitro Effects of Amphotericin B on Growth and Ultrastructure of the Amoeboflagellates Naegleria gruberi and Naegleria fowleri. Antimicrob. Agents Chemother. 1975, 47, 524–528. [Google Scholar] [CrossRef]
- Lee, K.K.; Karr, S.L.; Wong, M.M.; Hoeprich, P.D. In Vitro Susceptibilities of Naegleria fowleri Strain HB-1 to Selected Antimicrobial Agents, Singly and in Combination. Antimicrob. Agents Chemother. 1979, 16, 217–220. [Google Scholar] [CrossRef]
- Schuster, F.L.; Guglielmo, B.J.; Visvesvara, G.S. In-Vitro Activity of Miltefosine and Voriconazole on Clinical Isolates of Free-Living Amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri. J. Eukaryot. Microbiol. 2006, 53, 121–126. [Google Scholar] [CrossRef] [PubMed]
- Marschner, N.; Kotting, J.; Eibl, H.; Unger, C. Distribution of hexadecyl phosphocholine and octadecyl-methyl-glycero-3-phosphocholine in rat tissues during steady-state treatment. Cancer Chemother. Pharmacol. 1992, 31, 18–22. [Google Scholar] [CrossRef] [PubMed]
- Sundar, S.; Jha, T.K.; Thakur, C.P.; Engel, J.; Sindermann, H.; Fischer, C.; Junge, K.; Bryceson, A.; Berman, J. Oral miltefosine for Indian visceral leishmaniasis. N. Eng. J. Med. 2002, 347, 1739–1746. [Google Scholar] [CrossRef] [PubMed]
- Linam, W.M.; Ahmed, M.; Cope, J.R.; Chu, C.; Visvesvara, G.S.; Da Silva, A.J.; Qvarnstrom, Y.; Green, J. Successful Treatment of an Adolescent with Naegleria fowleri Primary Amebic Meningoencephalitis. Pediatrics 2015, 135, e744–e748. [Google Scholar] [CrossRef] [PubMed]
- Martínez, D.Y.; Bravo-Cossio, F.; Valdivia-Tapia, M.D.C.; Carreazo, N.Y.; Cabello-Vilchez, A.M. Successful Treatment of Primary Amoebic Meningoencephalitis Using a Novel Therapeutic Regimen Including Miltefosine and Voriconazole. Acta Parasit. 2022, 67, 1421–1424. [Google Scholar] [CrossRef]
- Nau, R.; Prange, H.W.; Menck, S.; Kolenda, H.; Visser, K.; Seydel, J.K. Penetration of rifampicin into the cerebrospinal fluid of adults with uninflamed meninges. J. Antimicrob. Chemother. 1992, 29, 719–724. [Google Scholar] [CrossRef] [PubMed]
- Kaojarern, S.; Supmonchai, K.; Phuapradit, P.; Mokkavesa, C.; Krittiyanunt, S. Effect of steroids on cerebrospinal fluid penetration of antituberculous drugs in tuberculous meningitis. Clin. Pharmacol. Ther. 1991, 49, 6–12. [Google Scholar] [CrossRef]
- Schwartz, S.; Thiel, E. Cerebral aspergillosis: Tissue penetration is the key. Med. Mycol. 2009, 47 (Suppl. S1), S387–S393. [Google Scholar] [CrossRef]
- Anwar, A.; Rajendran, K.; Siddiqui, R.; Shah, M.R.; Khan, N.A. Clinically Approved Drugs against CNS Diseases as Potential Therapeutic Agents to Target Brain-Eating Amoebae. ACS Chem. Neurosci. 2019, 10, 658–666. [Google Scholar] [CrossRef] [PubMed]
- Koren, G.; Barzilay, Z.; Schachar, E.; Brand, N.; Danee, S.; Halkin, H.; MacLeod, S.M. Kinetics of CSF Phenytoin in Children. Can. J. Neurol. Sci. 1983, 10, 195–197. [Google Scholar] [CrossRef]
- Felton, T.; Troke, P.F.; Hope, W.W. Tissue penetration of antifungal agents. Clin. Microbiol. Rev. 2014, 27, 68–88. [Google Scholar] [CrossRef] [PubMed]
- Debnath, A.; Calvet, C.M.; Jennings, G.; Zhou, W.; Aksenov, A.; Luth, M.R.; Abagyan, R.; Nes, W.D.; McKerrow, J.H.; Podust, L.M. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). PLoS Negl. Trop. Dis. 2017, 11, e0006104. [Google Scholar] [CrossRef]
- Perfect, J.R.; Durack, D.T. Penetration of imidazoles and triazoles into cerebrospinal fluid of rabbits. J. Antimicrob. Chemother. 1985, 16, 81–86. [Google Scholar] [CrossRef] [PubMed]
- Schmitt-Hoffmann, A.-H.; Kato, K.; Townsend, R.; Potchoiba, M.J.; Hope, W.W.; Andes, D.; Spickermann, J.; Schneidkraut, M.J. Tissue Distribution and Elimination of Isavuconazole following Single and Repeat Oral-Dose Administration of Isavuconazonium Sulfate to Rats. Antimicrob. Agents Chemother. 2017, 61, e01292-17. [Google Scholar] [CrossRef]
- Sorensen, K.N.; Sobel, R.A.; Clemons, K.V.; Pappagianis, D.; Stevens, D.A.; Williams, P.L. Comparison of fluconazole and itraconazole in a rabbit model of coccidioidal meningitis. Antimicrob. Agents Chemother. 2000, 44, 1512–1517. [Google Scholar] [CrossRef]
- Calcagno, A.; Baietto, L.; De Rosa, F.G.; Tettoni, M.C.; Libanore, V.; Bertucci, R.; D’Avolio, A.; Di Perri, G. Posaconazole cerebrospinal concentrations in an HIV-infected patient with brain mucormycosis. J. Antimicrob. Chemother. 2011, 66, 224–225. [Google Scholar] [CrossRef] [PubMed]
- Zhou, W.; Debnath, A.; Jennings, G.; Hahn, H.J.; Vanderloop, B.H.; Chaudhuri, M.; Nes, W.D.; Podust, L.M. Enzymatic chokepoints in the sterol biosynthesis pathway of Naegleria fowleri. PLoS Pathog. 2018, 14, e1007245. [Google Scholar] [CrossRef]
- Hahn, H.J.; Debnath, A. In Vitro Evaluation of Farnesyltransferase Inhibitor and its Effect in Combination with 3-Hydroxy-3-Methyl-Glutaryl-CoA Reductase Inhibitor against Naegleria fowleri. Pathogens 2020, 9, 689. [Google Scholar] [CrossRef]
- Hahn, H.J.; Abagyan, R.; Podust, L.M.; Roy, S.; Ali, I.K.M.; Debnath, A. HMG-CoA Reductase Inhibitors as Drug Leads against Naegleria fowleri. ACS Chem. Neurosci. 2020, 11, 3089–3096. [Google Scholar] [CrossRef]
- Joseph, S.K.; Arya, M.A.; Thomas, S.; Nair, S.C. Nanomedicine as a future therapeutic approach for treating meningitis. J. Drug Sci. Technol. 2022, 67, 102968. [Google Scholar] [CrossRef]
- Dakal, T.C.; Kumar, A.; Majumdar, R.S.; Yadav, V. Mechanistic Basis of Antimicrobial Actions of Silver Nanoparticles. Front. Microbiol. 2016, 7, 1831. [Google Scholar] [CrossRef]
- Rajendran, K.; Anwar, A.; Khan, N.A.; Siddiqui, R. Brain-Eating Amoebae: Silver Nanoparticle Conjugation Enhanced Efficacy of Anti-Amoebic Drugs against Naegleria fowleri. ACS Chem. Neurosci. 2017, 8, 2626–2630. [Google Scholar] [CrossRef] [PubMed]
- Anwar, A.; Masri, A.; Rao, K.; Rajendran, K.; Khan, N.A.; Shah, M.R.; Siddiqui, R. Antimicrobial activities of green synthesized gums-stabilized nanoparticles loaded with flavonoids. Sci. Rep. 2019, 9, 3122. [Google Scholar] [CrossRef] [PubMed]
- Mohan, Y.M.; Raju, K.M.; Sambasivudu, K.; Singh, S.; Sreedhar, B. Preparation of acacia-stabilized silver nanoparticles: A green approach. J. Appl. Polym. Sci. 2007, 106, 3375–3381. [Google Scholar] [CrossRef]
- Benfattoum, K.; Haddadine, N.; Bouslah, N.; Benaboura, A.; Maincent, P.; Barillé, R.; Sapin-Minet, A.; El-Shall, S. Formulation characterization and in vitro evaluation of acacia gum-calcium alginate beads for oral drug delivery systems. Polym. Adv. Technol. 2018, 29, 884–895. [Google Scholar] [CrossRef]
- Anwar, A.; Mungroo, M.R.; Anwar, A.; Sullivan, W.J.; Khan, N.A.; Siddiqui, R. Repositioning of Guanabenz in Conjugation with Gold and Silver Nanoparticles against Pathogenic Amoebae Acanthamoeba castellanii and Naegleria fowleri. ACS Infect. Dis. 2019, 5, 2039–2046. [Google Scholar] [CrossRef]
- Benmerzouga, I.; Checkley, L.A.; Ferdig, M.T.; Arrizabalaga, G.; Wek, R.C.; Sullivan, W.J. Guanabenz repurposed as an antiparasitic with activity against acute and latent toxoplasmosis. Antimicrob. Agents Chemother. 2015, 59, 6939–6945. [Google Scholar] [CrossRef]
- Martynowicz, J.; Augusto, L.; Wek, R.C.; Boehm, S.L.; Sullivan, W.J. Guanabenz Reverses a Key Behavioral Change Caused by Latent Toxoplasmosis in Mice by Reducing Neuroinflammation. mBio 2019, 10, e00381-19. [Google Scholar] [CrossRef]
- Daraee, H.; Eatemadi, A.; Abbasi, E.; Aval, S.F.; Kouhi, M.; Akbarzadeh, A. Application of gold nanoparticles in biomedical and drug delivery. Artif. Cells Nanomed. Biotechnol. 2016, 44, 410–422. [Google Scholar] [CrossRef] [PubMed]
- Rajendran, K.; Anwar, A.; Khan, N.A.; Shah, M.R.; Siddiqui, R. trans-Cinnamic Acid Conjugated Gold Nanoparticles as Potent Therapeutics against Brain-Eating Amoeba Naegleria fowleri. ACS Chem. Neurosci. 2019, 10, 2692–2696. [Google Scholar] [CrossRef] [PubMed]
- Mungroo, M.R.; Anwar, A.; Khan, N.A.; Siddiqui, R. Gold-Conjugated Curcumin as a Novel Therapeutic Agent against Brain-Eating Amoebae. ACS Omega 2020, 5, 12467–12475. [Google Scholar] [CrossRef] [PubMed]
- Abdelnasir, S.; Mungroo, M.R.; Shahabuddin, S.; Siddiqui, R.; Khan, N.A.; Anwar, A. Polyaniline-Conjugated Boron Nitride Nanoparticles Exhibiting Potent Effects against Pathogenic Brain-Eating Amoebae. ACS Chem. Neurosci. 2021, 12, 3579–3587. [Google Scholar] [CrossRef] [PubMed]
- Shang, E.; Niu, J.; Li, Y.; Zhou, Y.; Crittenden, J.C. Comparative toxicity of Cd, Mo, and W sulphide nanomaterials toward E. coli under UV irradiation. Environ. Pollut. 2017, 224, 606–614. [Google Scholar] [CrossRef]
- Agarwal, V.; Chatterjee, K. Recent advances in the field of transition metal dichalcogenides for biomedical applications. Nanoscale 2018, 10, 16365–16397. [Google Scholar] [CrossRef]
- Abdelnasir, S.; Mungroo, M.R.; Shahabuddin, S.; Siddiqui, R.; Khan, N.A.; Ahmad, I.; Anwar, A. Polyaniline (PANI)-conjugated tungsten disulphide (WS2) nanoparticles as potential therapeutic agents against brain-eating amoebae. Appl. Microbiol. Biotechnol. 2022, 106, 3279–3291. [Google Scholar] [CrossRef] [PubMed]
- Zhou, X.; Smith, Q.R.; Liu, X. Brain penetrating peptides and peptide-drug conjugates to overcome the blood-brain barrier and target CNS diseases. WIREs Nanomed. Nanobiotechnol. 2021, 13, e1695. [Google Scholar] [CrossRef]
- Oller-Salvia, B.; Sánchez-Navarro, M.; Giralt, E.; Teixidó, M. Blood-brain barrier shuttle peptides: An emerging paradigm for brain delivery. Chem. Soc. Rev. 2016, 45, 4690–4707. [Google Scholar] [CrossRef]
- Díaz-Perlas, C.; Sánchez-Navarro, M.; Oller-Salvia, B.; Moreno, M.; Teixidó, M.; Giralt, E. Phage display as a tool to discover blood-brain barrier (BBB)-shuttle peptides: Panning against a human BBB cellular model. Pept. Sci. 2017, 8, e22928. [Google Scholar] [CrossRef] [PubMed]
- Siddiqui, R.; Khan, N.A. Intranasal Route for the Delivery of Antiamebic Drugs Against brain-eating Amoeba. Ther. Deliv. 2023, 14, 175–177. [Google Scholar] [CrossRef]
- Khafagy, R.; Gupta, S.; Campisi, P.; Waters, V. Treatment of localized mucormycosis using nasal amphotericin B irrigation in pediatric oncology. Pediat. Blood Cancer 2020, 67, e28175. [Google Scholar] [CrossRef]
- Milanes, J.E.; Yan, V.C.; Pham, C.-D.; Muller, F.; Kwain, S.; Rees, K.C.; Dominy, B.N.; Whitehead, D.C.; Millward, S.W.; Bolejack, M.; et al. Enolase inhibitors as therapeutic leads for Naegleria fowleri infection. PLoS Pathog. 2024, 20, e1012412. [Google Scholar] [CrossRef] [PubMed]
- Xu, D.; Song, X.-J.; Chen, X.; Wang, J.-W.; Cui, Y.-L. Advances and future perspectives of intranasal drug delivery: A scientometric review. J. Control. Release 2024, 367, 366–384. [Google Scholar] [CrossRef]
- Keller, L.-A.; Merkel, O.; Popp, A. Intranasal drug delivery: Opportunities and toxicologic challenges during drug development. Drug Deliv. Transl. Res. 2022, 12, 735–757. [Google Scholar] [CrossRef]
- Rabiee, N.; Ahmadi, S.; Afshari, R.; Khalaji, S.; Rabiee, M.; Bagherzadeh, M.; Fatahi, Y.; Dinarvand, R.; Tahriri, M.; Tayebi, L.; et al. Polymeric Nanoparticles for Nasal Drug Delivery to the Brain: Relevance to Alzheimer’s Disease. Adv. Ther. 2020, 4, 2000076. [Google Scholar] [CrossRef]
- Luo, D.; Ni, X.; Yang, H.; Feng, L.; Chen, Z.; Bai, L. A comprehensive review of advanced nasal delivery: Specially insulin and calcitonin. Euro. J. Pharm. Sci. 2024, 192, 106630. [Google Scholar] [CrossRef]
Compound | Route of Administration and Dosage Information | Reference |
---|---|---|
Amphotericin B | Intravenous Day 1–3: 1.5 mg/kg/day in 2 divided doses Day 4–14: 1 mg/kg/day once daily OR Intrathecal Day 1–2: 1.5 mg once daily Day 3–0: 1 mg/day every other day | [12] |
Miltefosine | Oral Weight < 45 kg, 50 mg twice daily Weight > 45 kg, 50 mg thrice daily Duration: 28 days | [12] |
Fluconazole | Intravenous or oral 10 mg/kg/day once daily Duration: 28 days | [12] |
Rifampicin | Intravenous or oral 10 mg/kg/day once daily Duration: 28 days | [12] |
Azithromycin | Intravenous or oral 10 mg/kg/day once daily Duration: 28 days | [12] |
Dexamethasone | Intravenous 0.6 mg/kg/day in 4 divided doses Duration: 4 days | [12] |
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Fong, H.; Leid, Z.H.; Debnath, A. Approaches for Targeting Naegleria fowleri Using Nanoparticles and Artificial Peptides. Pathogens 2024, 13, 695. https://doi.org/10.3390/pathogens13080695
Fong H, Leid ZH, Debnath A. Approaches for Targeting Naegleria fowleri Using Nanoparticles and Artificial Peptides. Pathogens. 2024; 13(8):695. https://doi.org/10.3390/pathogens13080695
Chicago/Turabian StyleFong, Hayley, Zachary H. Leid, and Anjan Debnath. 2024. "Approaches for Targeting Naegleria fowleri Using Nanoparticles and Artificial Peptides" Pathogens 13, no. 8: 695. https://doi.org/10.3390/pathogens13080695