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

• Published in: Pharmaceutical research Vol. 36; no. 9; pp. 131 - 10
• Main Authors: de Oliveira Junior, Edilson Ribeiro, Nascimento, Thais Leite, Salomão, Mariana Arraes, da Silva, Artur Christian Garcia, Valadares, Marize Campos, Lima, Eliana Martins
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.09.2019; Springer; Springer Nature B.V
• Subjects: Administration, Intranasal; Administration, Oral; Analysis; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Brain; Brain - metabolism; Brain cancer; Brain tumors; Cell Line, Tumor; Central Nervous System Neoplasms - drug therapy; Cytotoxicity; Fluorescence; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma cells; Glioblastoma multiforme; Humans; Inhibitory Concentration 50; Intranasal administration; Male; Medical Law; Melatonin; Melatonin - administration & dosage; Melatonin - pharmacokinetics; Nanoparticles; Nanoparticles - chemistry; Nose; Oral administration; Pharmacology/Toxicology; Pharmacy; Polycaprolactone; Polyesters - chemistry; Rats, Wistar; Research Paper; Solubility; Tissue Distribution; Tomography; Translocation; Tumor cells; blood-brain barrier; brain delivery; fluorescence tomography; intranasal; nanoparticle translocation
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-019-2662-z

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 AUC brain 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.