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A topical gel nanoformulation of amphotericin B (AmB) for the treatment of cutaneous leishmaniasis (CL)

  • Original Paper: Nano-structured materials (particles, fibers, colloids, composites, etc.)
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Abstract

This study aimed to improve the water solubility and cutaneous permeability of Amphotericin B (AmB) for the topical treatment of Leishmania major-induced cutaneous leishmaniasis (CL) using two topical liposome- and polyethylene glycol (PEG)ylated liposome-gel formulations. The topical gel formulations of AmB were developed by its encapsulation into liposome (Lip-AmB) and (PEG)ylated liposome (PEG-Lip-AmB) using the reverse-phase evaporation method. The nanoformulations were characterized using dynamic light scattering and spectrophotometry. Their biological effects were evaluated in vitro and in vivo using Wright-Giemsa staining, limiting dilution assay, and pathological studies. Lip-AmB and PEG-Lip-AmB with the size of 257 ± 12.5 nm and 237 ± 12 nm, respectively, were synthesized. PEG-Lip-AmB compared to Lip-AmB, was more potent to decrease the drug toxicity and increase the drug’s therapeutic effects. The results of in vivo studies were in agreement with the results of in vitro studies, in which PEG-Lip-AmB-loaded gel (PEG-Lip-AmB-Gel), compared to Lip-AmB-loaded gel, could decrease the lesion size and parasite burden by 1.7- and 1.6-fold, respectively. These results suggest PEG-Lip-AmB-Gel can be used as a promising carrier to improve the properties of AmB for topical application against CL.

Graphical Abstract

Highlights

  • PEGylated liposome significantly decreased the toxicity of Amphotericin B in vitro

  • PEGylated liposome significantly increased the killing effects of Amphotericin B against leishmania major in vitro

  • Loading of Amphotericin B into PEGylated liposome caused a significant reduction in lesion size and parasite burden in vivo

  • Loading of Amphotericin B into PEGylated liposome could significantly reduce the renal toxicity of the drug in vivo

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Lanza JS, Pomel S, Loiseau PM, Frézard F (2019) Recent advances in amphotericin B delivery strategies for the treatment of leishmaniases. Expert Opin drug Deliv 16(10):1063–1079

    Article  CAS  Google Scholar 

  2. Majumder S, Das N, Pandey N, Srivastava T, Ghosha D (2018) Synthesis, characterization of novel PLGA encapsulated indole nanoparticles and study of its cytotoxic potential against A549 lung cancer cell line. J Appl Pharm Sci 8(08):144–150

    CAS  Google Scholar 

  3. Mostafavi M, Sharifi I, Farajzadeh S, Khazaeli P, Sharifi H, Pourseyedi E, Kakooei S, Bamorovat M, Keyhani A, Parizi MH (2019) Niosomal formulation of amphotericin B alone and in combination with glucantime: in vitro and in vivo leishmanicidal effects. Biomedicine Pharmacother 116:108942

    Article  CAS  Google Scholar 

  4. Lalatsa A, Statts L, de Jesus JA, Adewusi O, Dea-Ayuela MA, Bolas-Fernandez F, Laurenti MD, Passero LFD, Serrano DR (2020) Topical buparvaquone nano-enabled hydrogels for cutaneous leishmaniasis. Int J Pharmaceutics 588:119734

    Article  CAS  Google Scholar 

  5. Alvar J, Vélez ID, Bern C, Herrero M, Desjeux P, Cano J, Jannin J, den Boer M, Team WLC (2012) Leishmaniasis worldwide and global estimates of its incidence. PloS one 7(5):e35671

    Article  CAS  Google Scholar 

  6. Wijnant G-J, Van Bocxlaer K, Yardley V, Harris A, Murdan S, Croft SL (2017) AmBisome® treatment of murine cutaneous leishmaniasis: relation between skin pharmacokinetics and efficacy. Antimicrob Agents Chemother

  7. Fernández-García R, Statts L, de Jesus JA, Dea-Ayuela MA, Bautista L, Simao R, Bolas-Fernandez F, Ballesteros MP, Laurenti MD, Passero LF (2020) Ultradeformable lipid vesicles localize amphotericin B in the dermis for the treatment of infectious skin diseases. ACS Infect Dis 6(10):2647–2660

    Article  Google Scholar 

  8. Ammar AA, Nasereddin A, Ereqat S, Dan-Goor M, Jaffe CL, Zussman E, Abdeen Z (2019) Amphotericin B-loaded nanoparticles for local treatment of cutaneous leishmaniasis. Drug Deliv Transl Res 9(1):76–84

    Article  Google Scholar 

  9. Zahin N, Anwar R, Tewari D, Kabir M, Sajid A, Mathew B, Uddin M, Aleya L, Abdel-Daim MM (2020) Nanoparticles and its biomedical applications in health and diseases: special focus on drug delivery. Environ Sci Pollut Res 27(16):19151–19168

    Article  CAS  Google Scholar 

  10. Alavi SE, Ebrahimi Shahmabadi H (2021) Anthelmintics for drug repurposing: opportunities and challenges. Saudi. Pharm J: SPJ 29(5):434

    CAS  Google Scholar 

  11. Alavi SE, Raza A, Koohi Moftakhari Esfahani M, Akbarzadeh A, Abdollahi SH, Ebrahimi Shahmabadi H (2022) Carboplatin niosomal nanoplatform for potentiated chemotherapy. J Pharm Sci

  12. Koohi Moftakhari Esfahani M, Alavi SE, Cabot PJ, Islam N, Izake EL (2022) β-Lactoglobulin-modified mesoporous silica nanoparticles: a promising carrier for the targeted delivery of fenbendazole into prostate cancer cells. Pharmaceutics 14(4):884

    Article  CAS  Google Scholar 

  13. Ghaferi M, Koohi Moftakhari Esfahani M, Raza A, Al Harthi S, Ebrahimi Shahmabadi H, Alavi SE (2021) Mesoporous silica nanoparticles: synthesis methods and their therapeutic use-recent advances. J Drug Target 29(2):131–154

    Article  CAS  Google Scholar 

  14. Ghaferi M, Amari S, Vivek Mohrir B, Raza A, Ebrahimi Shahmabadi H, Alavi SE (2020) Preparation, characterization, and evaluation of cisplatin-loaded polybutylcyanoacrylate nanoparticles with improved in vitro and in vivo anticancer activities. Pharmaceuticals 13(3):44

    Article  CAS  Google Scholar 

  15. Koohi Moftakhari Esfahani M, Alavi SE, Shahbazian S, Ebrahimi Shahmabadi H (2018) Drug delivery of cisplatin to breast cancer by polybutylcyanoacrylate nanoparticles. Adv Polym Technol 37(3):674–678

    Article  CAS  Google Scholar 

  16. Ghaferi M, Zahra W, Akbarzadeh A, Ebrahimi Shahmabadi H, Alavi SE (2022) Enhancing the efficacy of albendazole for liver cancer treatment using mesoporous silica nanoparticles: an in vitro study. EXCLI J 21:236–249

    Google Scholar 

  17. Alavi SE, Raza A, Gholami M, Giles M, Al-Sammak R, Ibrahim A, Ebrahimi Shahmabadi H, Sharma LA(2022) Advanced drug delivery platforms for the treatment of oral pathogen. Pharmaceutics 14(11):2293

    Article  CAS  Google Scholar 

  18. Koohi Moftakhari Esfahani M, Alavi SE, Cabot PJ, Islam N, Izake EL (2021) PEGylated mesoporous silica nanoparticles (mcm-41): a promising carrier for the targeted delivery of fenbendazole into prostrate cancer cells. Pharmaceutics 13(10):1605

    Article  Google Scholar 

  19. Hatamihanza H, Alavi SE, Ebrahimi Shahmabadi H, Akbarzadeh A (2020) Preparation, characterization and immunostimulatory effects of CRD2 and CRD3 from TNF Receptor-1 encapsulated into pegylated liposomal nanoparticles. Int J Pept Res Ther 26(2):745–753

    Article  CAS  Google Scholar 

  20. Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R (2021) Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 20(2):101–124

    Article  CAS  Google Scholar 

  21. Alavi SE, Koohi Moftakhari Esfahani M, Ghassemi S, Akbarzadeh A, Hassanshahi G (2014) In vitro evaluation of the efficacy of liposomal and pegylated liposomal hydroxyurea. Indian J Clin Biochem 29(1):84–88

    Article  CAS  Google Scholar 

  22. Alavi SE, Koohi Moftakhari Esfahani M, Raza A, Adelnia H, Ebrahimi Shahmabadi H (2022) PEG-grafted liposomes for enhanced antibacterial and antibiotic activities: an in vivo study. NanoImpact:100384

  23. Pérez-Herrero E, Fernández-Medarde A (2015) Advanced targeted therapies in cancer: drug nanocarriers, the future of chemotherapy. Eur J pharm biopharm 93:52–79

    Article  Google Scholar 

  24. Mishra GP, Bagui M, Tamboli V, Mitra AK (2011) Recent applications of liposomes in ophthalmic drug delivery. J Drug Deliv 2011

  25. Lamichhane N, Udayakumar TS, D’Souza WD, Simone II CB, Raghavan SR, Polf J, Mahmood J (2018) Liposomes: clinical applications and potential for image-guided drug delivery. Molecules 23(2):288

    Article  Google Scholar 

  26. Ghaferi M, Asadollahzadeh MJ, Akbarzadeh A, Ebrahimi Shahmabadi H, Alavi SE (2020) Enhanced efficacy of PEGylated liposomal cisplatin: In vitro and in vivo evaluation. Int J Mol Sci 21(2):559

    Article  CAS  Google Scholar 

  27. Movahedi F, Ebrahimi Shahmabadi H, Alavi SE, Koohi Moftakhari Esfahani M (2014) Release modeling and comparison of nanoarchaeosomal, nanoliposomal and pegylated nanoliposomal carriers for paclitaxel. Tumor Biol 35(9):8665–8672

    Article  CAS  Google Scholar 

  28. Ghaferi M, Raza A, Koohi M, Zahra W, Akbarzadeh A, Ebrahimi Shahmabadi H, Alavi SE (2022) Impact of PEGylated liposomal doxorubicin and carboplatin combination on glioblastoma. Pharmaceutics 14(10):2183

    Article  CAS  Google Scholar 

  29. Alavi SE, Cabot PJ, Raza A, Moyle PM (2021) Developing GLP-1 conjugated self-assembling nanofibers using copper-catalyzed alkyne–azide cycloaddition and evaluation of their biological activity. Bioconjugate Chem 32(4):810–820

    Article  CAS  Google Scholar 

  30. Alavi SE, Cabot PJ, Yap GY, Moyle PM (2020) Optimized methods for the production and bioconjugation of site-specific, alkyne-modified glucagon-like peptide-1 (GLP-1) analogs to azide-modified delivery platforms using copper-catalyzed alkyne–azide cycloaddition. Bioconjugate Chem 31(7):1820–1834

    Article  CAS  Google Scholar 

  31. Alavi SE, Panah N, Page F, Gholami M, Dastfal A, Sharma LA, Shahmabadi HE (2022) Hydrogel-based therapeutic coatings for dental implants. Eur Polym J 181:111652

  32. Jain S, Kumar D, Swarnakar NK, Thanki K (2012) Polyelectrolyte stabilized multilayered liposomes for oral delivery of paclitaxel. Biomaterials 33(28):6758–6768. https://doi.org/10.1016/j.biomaterials.2012.05.026

    Article  CAS  Google Scholar 

  33. Shaikh MS, Kale MA (2020) Formulation and molecular docking simulation study of luliconazole nanosuspension–based nanogel for transdermal drug delivery using modified polymer. Materials Today. Chemistry 18:100364

    CAS  Google Scholar 

  34. Panonnummal R, Jayakumar R, Sabitha M (2017) Comparative anti-psoriatic efficacy studies of clobetasol loaded chitin nanogel and marketed cream. Eur J Pharm Sci 96:193–206

    Article  CAS  Google Scholar 

  35. Kavian Z, Alavizadeh SH, Golmohamadzadeh S, Badiee A, Khamesipour A, Jaafari MR (2019) Development of topical liposomes containing miltefosine for the treatment of Leishmania major infection in susceptible BALB/c mice. Acta tropica 196:142–149

    Article  CAS  Google Scholar 

  36. Tavares GS, Mendonça DV, Miyazaki CK, Lage DP, Soyer TG, Carvalho LM, Ottoni FM, Dias DS, Ribeiro PA, Antinarelli LM (2019) A Pluronic® F127-based polymeric micelle system containing an antileishmanial molecule is immunotherapeutic and effective in the treatment against Leishmania amazonensis infection. Parasitol Int 68(1):63–72

    Article  CAS  Google Scholar 

  37. Bhagat V, Pandit RA, Ambapurkar S, Sengar M, Kulkarni AP (2021) Drug interactions between antimicrobial and immunosuppressive agents in solid organ transplant recipients. Indian J Crit Care Med: Peer-reviewed, Off Publ Indian Soc Crit Care Med 25(1):67

    Article  CAS  Google Scholar 

  38. Budai L, Kaszás N, Gróf P, Lenti K, Maghami K, Antal I, Klebovich I, Petrikovics I, Budai M (2013) Liposomes for topical use: a physico-chemical comparison of vesicles prepared from egg or soy lecithin. Sci pharmaceutica 81(4):1151–1166

    Article  CAS  Google Scholar 

  39. Zhong J, Huang H-L, Li J, Qian F-C, Li L-Q, Niu P-P, Dai L-C (2015) Development of hybrid-type modified chitosan derivative nanoparticles for the intracellular delivery of midkine-siRNA in hepatocellular carcinoma cells. Hepatobiliary Pancreat Dis Int 14(1):82–89

    Article  Google Scholar 

  40. Liu M, Zhang X, Yang B, Deng F, Ji J, Yang Y, Huang Z, Zhang X, Wei Y (2014) Luminescence tunable fluorescent organic nanoparticles from polyethyleneimine and maltose: facile preparation and bioimaging applications. RSC Adv 4(43):22294–22298

    Article  CAS  Google Scholar 

  41. Najlah M, Said Suliman A, Tolaymat I, Kurusamy S, Kannappan V, Elhissi A, Wang W (2019) Development of injectable PEGylated liposome encapsulating disulfiram for colorectal cancer treatment. Pharmaceutics 11(11):610

    Article  CAS  Google Scholar 

  42. Abbina S, Parambath A (2018) PEGylation and its alternatives: a summary. Engineering of biomaterials for drug delivery systems. elsevier, pp 363–376

  43. Jiao Y, Li D, Liu C, Chang Y, Song J, Xiao Y (2018) Polypeptide–decorated nanoliposomes as novel delivery systems for lutein. RSC Adv 8(55):31372–31381

    Article  CAS  Google Scholar 

  44. Worldwide MI (2011) Dynamic light scattering, common terms defined. Inform white paper malvern, UK: malvern Instruments Limited:1–6

  45. Gnoatto JA, Morás AM, de Oliveira JV, Arndt E, Dallegrave A, da Cunha ACB, Moura DJ, dos Santos JHZ (2022) PEGylated and zwitterated silica nanoparticles as doxorubicin carriers applied in a breast cancer cell line: effects on protein corona formation. J Drug Deliv Sci Technol 71:103325

    Article  CAS  Google Scholar 

  46. Musumeci T, Bonaccorso A, Carbone C, Russo G, Pappalardo F, Puglisi G (2019) Design and optimization of PEGylated nanoparticles intended for Berberine Chloride delivery. J Drug Deliv Sci Technol 52:521–530. https://doi.org/10.1016/j.jddst.2019.05.012

    Article  CAS  Google Scholar 

  47. Kang B-S, Choi J-S, Lee S-E, Lee J-K, Kim T-H, Jang WS, Tunsirikongkon A, Kim J-K, Park J-S (2017) Enhancing the in vitro anticancer activity of albendazole incorporated into chitosan-coated PLGA nanoparticles. Carbohydr Polym 159:39–47

    Article  CAS  Google Scholar 

  48. Tyrrell ZL, Shen Y, Radosz M (2010) Fabrication of micellar nanoparticles for drug delivery through the self-assembly of block copolymers. Prog Polym Sci 35(9):1128–1143

    Article  CAS  Google Scholar 

  49. Cai D, Gao W, He B, Dai W, Zhang H, Wang X, Wang J, Zhang X, Zhang Q (2014) Hydrophobic penetrating peptide PFVYLI-modified stealth liposomes for doxorubicin delivery in breast cancer therapy. Biomaterials 35(7):2283–2294

    Article  CAS  Google Scholar 

  50. Wolfram J, Zhu M, Yang Y, Shen J, Gentile E, Paolino D, Fresta M, Nie G, Chen C, Shen H (2014) Safety of nanoparticles in medicine. Curr Drug Targets 15:1–3

    Google Scholar 

  51. Alavi SE, Muflih Al Harthi S, Ebrahimi Shahmabadi H, Akbarzadeh A (2019) Cisplatin-loaded polybutylcyanoacrylate nanoparticles with improved properties as an anticancer agent. Int J Mol Sci 20(7):1531

    Article  CAS  Google Scholar 

  52. Yu L, Dong A, Guo R, Yang M, Deng L, Zhang J (2018) DOX/ICG coencapsulated liposome-coated thermosensitive nanogels for NIR-triggered simultaneous drug release and photothermal effect. ACS Biomater Sci Eng 4(7):2424–2434

    Article  CAS  Google Scholar 

  53. Jaafari MR, Hatamipour M, Alavizadeh SH, Abbasi A, Saberi Z, Rafati S, Taslimi Y, Mohammadi AM, Khamesipour A (2019) Development of a topical liposomal formulation of Amphotericin B for the treatment of cutaneous leishmaniasis. Int J parasitology: drugs drug resistance 11:156–165

    Google Scholar 

  54. Alavi SE, Ebrahimi Shahmabadi H (2021) GLP-1 peptide analogs for targeting pancreatic beta cells. Drug Discov Today

  55. Rangsimawong W, Opanasopit P, Rojanarata T, Duangjit S, Ngawhirunpat T (2016) Skin transport of hydrophilic compound-loaded PEGylated lipid nanocarriers: comparative study of liposomes, niosomes, and solid lipid nanoparticles. Biol Pharm Bull 39(8):1254–1262

    Article  CAS  Google Scholar 

  56. El Maghraby GM, Williams AC (2009) Vesicular systems for delivering conventional small organic molecules and larger macromolecules to and through human skin. Expert Opin Drug Deliv 6(2):149–163

    Article  CAS  Google Scholar 

  57. Knudsen NØ, Rønholt S, Salte RD, Jorgensen L, Thormann T, Basse LH, Hansen J, Frokjaer S, Foged C (2012) Calcipotriol delivery into the skin with PEGylated liposomes. Eur J Pharmaceutics Biopharmaceutics 81(3):532–539

    Article  CAS  Google Scholar 

  58. Immordino ML, Dosio F, Cattel L (2006) Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomed 1(3):297

    CAS  Google Scholar 

  59. Moribe K, Shibata M, Furuishi T, Higashi K, Tomono K, Yamamoto K (2010) Effect of particle size on skin permeation and retention of piroxicam in aqueous suspension. Chem Pharm Bull 58(8):1096–1099

    Article  CAS  Google Scholar 

  60. Gonzalez LE, Boylan PM (2021) Netarsudil for the treatment of open-angle glaucoma and ocular hypertension: a literature review. Ann Pharmacother 55(8):1025–1036

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by the School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran, and we would like to show our gratitude to the colleagues for their support.

Author contributions

Conceptualization: HES and SEA, methodology: RB, software: SA, validation: RB and MBG, formal analysis: SA, investigation: RB, resources: SA, data curation: SEA, writing—original draft preparation: RB and HES, writing—review and editing: SA, MBG and SEA, visualization: SEA and MBG, supervision: SEA and HES. All authors have read and agreed to the published version of the manuscript.

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Boshrouyeh, R., Amari, S., Boshrouyeh Ghandashtani, M. et al. A topical gel nanoformulation of amphotericin B (AmB) for the treatment of cutaneous leishmaniasis (CL). J Sol-Gel Sci Technol 105, 768–780 (2023). https://doi.org/10.1007/s10971-023-06041-w

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  • DOI: https://doi.org/10.1007/s10971-023-06041-w

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