Mechanisms of the effectiveness of poly(epsilon-caprolactone) lipid-core nanocapsules loaded with methotrexate on glioblastoma multiforme treatment

Autor(es)

Claret Pereira, Natalia Rubio ^[1] ; Loiola, Rodrigo Azevedo ^[1] ; Rodrigues, Stephen Fernandes ^[1] ; de Oliveira, Catiuscia P. ^[2] ; Buttenbender, Sabrina L. ^[3] ; Guterres, Silvia S. ^[2] ; Pohlmann, Adriana R. ^[3] ; Farsky, Sandra H. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Dept Clin & Toxicol Anal, 580 Cidade Univ, BR-05508000 Sao Paulo, SP - Brazil

^[2] Univ Fed Rio Grande do Sul, Fac Pharm, Porto Alegre, RS - Brazil

^[3] Univ Fed Rio Grande do Sul, Inst Chem, Dept Organ Chem, Porto Alegre, RS - Brazil

• Tipo de documento: Artigo Científico
• Fonte: INTERNATIONAL JOURNAL OF NANOMEDICINE; v. 13, p. 4563-4573, 2018.
• Citações Web of Science: 3

Resumo

Purpose: The low penetration of drugs across the blood-brain barrier (BBB) compromises the delivery of chemotherapeutic agents to the brain parenchyma and contributes to the poor prognosis of glioblastoma multiforme (GBM). We investigated the efficacy of methotrexate-loaded lipid-core nanocapsules (MTX-LNC) administered by the oral route to treat murine GBM, its ability to cross the BBB, and the mechanisms of MTX-LNC uptake by cultured GL261 glioma and BV2 microglia cells. Materials and methods: Female C57B/6 mice were used in intravital microscopy assays to investigate the penetrance of rhodamine B-label MTX-LNC (RhoB/MTX-LNC) in the brain after oral or IV administration, and to evaluate the BBB integrity. Intracranial implantation of GL261 cells was undertaken to induce a murine GBM model, and the effectiveness of oral MTX or MTX-LNC treatments (started on Day 10 of GBM, every 2 days for 12 days) was quantified by tumor size, body weight, and leukogram. Pharmacological blockade of endocytic pathways was done to investigate the mechanisms of MTX-LNC uptake by cultured GL261 and microglia BV2 cells by using fluorescence microscopy. The effect of MTX-LNC or MTX on GL261 and BV2 proliferation was evaluated to compare the cytotoxicity of such compounds. Results: RhoB/MTX-LNC was detected in brain parenchyma of mice after IV or oral administration, without any damage on BBB. Oral treatment with MTX-LNC reduced tumor volume and prevented weight loss and leukopenia in comparison to MTX-treated mice. MTX-LNC uptake by GL261 is caveolae-dependent, whereas endocytosis of MTX-LNC by BV2 occurs via phagocytosis and macropinocytosis. Both MTX-LNC and MTX reduced GL261 and BV2 proliferation; however, MTX-LNC showed higher efficacy in the inhibition of glioma proliferation. Conclusion: Together, we infer that the higher ability of MTX-LNC to cross the BBB and be captured by cancer and immune brain cells by different mechanisms is responsible for the higher efficacy of oral MTX-LNC treatment in GBM. (AU)

• Processo FAPESP: 11/02438-8 - Eficácia terapêutica de nanocápsulas de indometacina e éster etílico de indometacina na microcirculação cerebral de camundongos: estudos in vivo e ex vivo
• Beneficiário: Stephen Fernandes de Paula Rodrigues
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 14/07328-4 - Identificação de vias endógenas para o controle da inflamação
• Beneficiário: Sandra Helena Poliselli Farsky
• Modalidade de apoio: Auxílio à Pesquisa - Temático