In vivo biodistribution of venlafaxine-PLGA nanoparticles for brain delivery: plain vs. functionalized nanoparticles

ABSTRACT

Background: Actually, no drugs provide therapeutic benefit to approximately one-third of depressed patients. Depression is predicted to become the first global disease by 2030. So, new therapeutic interventions are imperative.

Research design and methods: Venlafaxine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were surface functionalized with two ligands against transferrin receptor to enhance access to brain. An in vitro blood–brain barrier model using hCMEC/D3 cell line was developed to evaluate permeability. In vivo biodistribution studies were performed using C57/bl6 mice. Particles were administered intranasal and main organs were analyzed.

Results: Particles were obtained as a lyophilized powder easily to re-suspend. Internalization and permeability studies showed the following cell association sequence: TfRp-NPs>Tf-NPs>plain NPs. Permeability studies also showed that encapsulated VLF was not affected by P-gP pump efflux increasing its concentration in the basolateral side after 24 h. In vivo studies showed that 25% of plain NPs reach the brain after 30 min of one intranasal administration while less than 5% of functionalized NPs get the target.

Conclusions: Plain NPs showed the highest ability to reach the brain vs. functionalized NPs after 30 min by intranasal administration. We suggest plain NPs probably travel via direct nose-to-brian route whereas functionalized NPs reach the brain by receptor-mediated endocytosis.

KEYWORDS:

• Depression
• PLGA nanoparticles
• venlafaxine
• blood–brain barrier
• transferrin receptor
• nose-to-brain

Author contributions

MD Cayero-Otero contributed on data collection, analysis and interpretation of the data of all in vitro and in vivo assays. MJ Gomes and C Martins mainly participated on data collection and analysis of cell assays. J Alvarez-Fuentes contributed on the design of analytical assays and statistical analysis. B Sarmento, M Fernandez-A’valo and L Martin-Banderas contributed to the idea and design of the study analysis and interpretation of the data. L Martin-Banderas contributed also on data collection and interpretation of in vivo data. MD Cayero-Otero, J Alvarez-Fuentes, B Sarmento and L Martin-Banderas have worked on the writing of the article and the critical review of its substantial intellectual content.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was partially founded by the Project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme [NORTE 2020], under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was co-financed by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/ Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” [POCI-01-0145-FEDER-007274].