Evaluation of in vitro and in vivo Efficacy of a Novel Amphotericin B-Loaded Nanostructured Lipid Carrier in the Treatment of Leishmania braziliensis Infection

Autor(es)

Reboucas-Silva, Jessica ^{[1, 2]} ; Tadini, Maraine Catarina ^{[3, 4]} ; Devequi-Nunes, Danielle ^{[1, 5]} ; Mansur, Ana Luiza ^[4] ; Silveira-Mattos, Paulo S. ^{[1, 2]} ; de Oliveira, Camila I. ^{[2, 6]} ; Formiga, Fabio R. ^{[7, 8]} ; Berretta, Andresa A. ^[9] ; Marquele-Oliveira, Franciane ^[4] ; Borges, Valeria M. ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Fundacao Oswaldo Cruz, Goncalo Moniz Inst, Lab Inflammat & Biomarkers, Salvador, BA - Brazil

^[2] Fed Univ Bahia UFBA, Fac Med Bahia, Postgrad Program Pathol, Salvador, BA - Brazil

^[3] Univ Sao Paulo, Dept Chem, Fac Philosophy Sci & Letters Ribeirao Preto, Ribeirao Preto, SP - Brazil

^[4] Eleve Sci Res & Dev, Sao Paulo - Brazil

^[5] SENAI Inst Innovat Adv Hlth Syst, Lab Pharmaceut Formulat, Salvador, BA - Brazil

^[6] Fundacao Oswaldo Cruz, Lab Vector Borne Infect Dis, Goncalo Moniz Inst, Salvador, BA - Brazil

^[7] Oswaldo Cruz Fdn FIOCRUZ, Aggeu Magalhaes Inst, Recife, PE - Brazil

^[8] Univ Pernambuco UPE, Postgrad Program Appl Cellular & Mol Biol, Recife, PE - Brazil

^[9] Apis Flora Ind & Comercial Ltda, Lab Res Dev & Innovat, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF NANOMEDICINE; v. 15, p. 8659-8672, 2020.
• Citações Web of Science: 0

Resumo

Background: Leishmaniasis is a neglected disease, and the current therapeutic arsenal for its treatment is seriously limited by high cost and toxicity. Nanostructured lipid carriers (NLCs) represent a promising approach due to high drug loading capacity, controlled drug release profiles and superior stability. Here, we explore the efficacy of a unique pH-sensitive amphotericin B-loaded NLC (AmB-NLC) in Leishmania braziliensis infection in vitro and in vivo. Methods and Results: AmB-NLC was assessed by dynamic light scattering and atomic force microscopy assays. The carrier showed a spherical shape with a nanometric size of 242.0 +/- 18.3 nm. Zeta potential was suggestive of high carrier stability (-42.5 +/- 1.5 mV), and the NLC showed similar to 99% drug encapsulation efficiency (EE%). In biological assays, AmB-NLC presented a similar IC50 as free AmB and conventional AmB deoxycholate (AmB-D) (11.7 +/- 1.73; 5.3 +/- 0.55 and 13 +/- 0.57 ng/mL, respectively), while also presenting higher selectivity index and lower toxicity to host cells, with no observed production of nitric oxide or TNF-alpha by in vitro assay. Confocal microscopy revealed the rapid uptake of AmB-NLC by infected macrophages after 1h, which, in association with more rapid disruption of AmB-NLC at acidic pH levels, may directly affect intracellular parasites. Leishmanicidal effects were evaluated in vivo in BALB/c mice infected in the ear dermis with L. braziliensis and treated with a pentavalent antimonial (Sb5+), liposomal AmB (AmB-L) or AmB-NLC. After 6 weeks of infection, AmB-NLC treatment resulted in smaller ear lesion size in all treated mice, indicating the efficacy of the novel formulation. Conclusion: Here, we preliminarily demonstrate the effectiveness of an innovative and cost-effective AmB-NLC formulation in promoting the killing of intracellular L. braziliensis. This novel carrier system could be a promising alternative for the future treatment of cutaneous leishmaniasis. (AU)

• Processo FAPESP: 15/15948-5 - Desenvolvimento e caracterização de medicamento de base nanotecnológica, alvo-dirigido, para tratamento de leishmaniose
• Beneficiário: Franciane Marquele de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisa Inovativa em Pequenas Empresas - PIPE
• Processo FAPESP: 17/22888-4 - Desenvolvimento e caracterização de medicamento de base nanotecnológica, alvo-dirigido, para tratamento de Leishmaniose
• Beneficiário: Franciane Marquele de Oliveira
• Modalidade de apoio: Auxílio à Pesquisa - Pesquisa Inovativa em Pequenas Empresas - PIPE
• Processo FAPESP: 16/10145-4 - Desenvolvimento e caracterização de medicamento de base nanotecnológica, alvo-dirigido, para tratamento de leishmaniose
• Beneficiário: Franciane Marquele de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Pesquisa Inovativa em Pequenas Empresas - PIPE
• Processo FAPESP: 16/11116-8 - Obtenção de sistemas nanoparticulados baseados em lipídeos e estudo de segurança em fibroblastos in vitro
• Beneficiário: Maraine Catarina Tadini
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico
• Processo FAPESP: 16/10345-3 - Validação do método de quantificação da Anf B em Sistemas Nanopartículados baseados em lipídeos
• Beneficiário: Ana Maria de Freitas Pinheiro
• Modalidade de apoio: Bolsas no Brasil - Programa Capacitação - Treinamento Técnico