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Increased Nose-to-Brain Delivery of Melatonin Mediated by Polycaprolactone Nanoparticles for the Treatment of Glioblastoma

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Abstract

Purpose

Intranasal administration has been extensively applied to deliver drugs to the brain. In spite of its unfavorable biopharmaceutic properties, melatonin (MLT) has demonstrated anticancer effects against glioblastoma. This study describes the nose-to-brain delivery of MLT-loaded polycaprolactone nanoparticles (MLT-NP) for the treatment of glioblastoma.

Methods

MLT-NP were prepared by nanoprecipitation. Following intranasal administration in rats, brain targeting of the formulation was demonstrated by fluorescence tomography. Brain and plasma pharmacokinetic profiles were analyzed. Cytotoxicity against U87MG glioblastoma cells and MRC-5 non-tumor cells was evaluated.

Results

MLT-NP increased the drug apparent water solubility ~35 fold. The formulation demonstrated strong activity against U87MG cells, resulting in IC50 ~2500 fold lower than that of the free drug. No cytotoxic effect was observed against non-tumor cells. Fluorescence tomography images evidenced the direct translocation of nanoparticles from nasal cavity to the brain. Intranasal administration of MLT-NP resulted in higher AUCbrain and drug targeting index compared to the free drug by either intranasal or oral route.

Conclusions

Nanoencapsulation of MLT was crucial for the selective antitumoral activity against U87MG. In vivo evaluation confirmed nose-to-brain delivery of MLT mediated by nanoparticles, highlighting the formulation as a suitable approach to improve glioblastoma therapy.

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Abbreviations

BBB:

Blood brain barrier

Cou6-NP:

Coumarin6-loaded nanoparticles

DTI:

Drug targeting index

EE%:

Encapsulation efficiency

FMT:

Fluorescence molecular tomography

GBM:

Glioblastoma multiforme

IR780-NP:

IR780-loaded nanoparticles

IS:

Internal standard

MLT:

Melatonin

MLT-NP:

Melatonin-loaded nanoparticles

MLT-susp:

Melatonin suspension

PCL:

Polycaprolactone

Pdi:

Polydispersity index

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Acknowledgments and Disclosures

This work was supported by the following Brazilian research funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Financiadora de Estudos e Pesquisas (FINEP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Financing code 001, Fundação de Apoio à Pesquisa da Universidade Federal de Goiás (FUNAPE) and Fundação de Apoio à Pesquisa do Estado de Goiás (FAPEG). The authors report no conflicts of interest in this work.

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Authors and Affiliations

  1. Laboratório de Nanotecnologia Farmacêutica e Sistemas de Liberação de Fármacos, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás – UFG, FarmaTec – 5ª Avenida c/Rua 240 s/n, Praça Universitária, Goiânia, GO, 74605-170, Brazil

    Edilson Ribeiro de Oliveira Junior, Thais Leite Nascimento, Mariana Arraes Salomão & Eliana Martins Lima

  2. Laboratório de Ensino e Pesquisa em Toxicologia in vitro, Tox-In, FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás - UFG, Goiânia, GO, Brazil

    Artur Christian Garcia da Silva & Marize Campos Valadares

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  1. Edilson Ribeiro de Oliveira Junior
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Correspondence to Eliana Martins Lima.

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de Oliveira Junior, E.R., Nascimento, T.L., Salomão, M.A. et al. Increased Nose-to-Brain Delivery of Melatonin Mediated by Polycaprolactone Nanoparticles for the Treatment of Glioblastoma. Pharm Res 36, 131 (2019). https://doi.org/10.1007/s11095-019-2662-z

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