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Modulating chitosan-PLGA nanoparticle properties to design a co-delivery platform for glioblastoma therapy intended for nose-to-brain route

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Abstract

Nose-to-brain delivery is a promising approach to target drugs into the brain, avoiding the blood-brain barrier and other drawbacks related to systemic absorption, and enabling an effective and safer treatment of diseases such as glioblastoma (GBM). Innovative materials and technologies that improve residence time in the nasal cavity and modulate biological interactions represent a great advance in this field. Mucoadhesive nanoparticles (NPs) based on poly(lactic-co-glycolic acid) (PLGA) and oligomeric chitosan (OCS) were designed as a rational strategy and potential platform to co-deliver alpha-cyano-4-hydroxycinnamic acid (CHC) and the monoclonal antibody cetuximab (CTX) into the brain, by nasal administration. The influence of formulation and process variables (O/Aq volume ratio, Pluronic concentration, PLGA concentration, and sonication time) on the properties of CHC-loaded NPs (size, zeta potential, PDI and entrapment efficiency) was investigated by a two-level full factorial design (24). Round, stable nano-sized particles (213–875 nm) with high positive surface charge (+ 33.2 to + 58.9 mV) and entrapment efficiency (75.69 to 93.23%) were produced by the emulsification/evaporation technique. Optimal process conditions were rationally selected based on a set of critical NP attributes (258 nm, + 37 mV, and 88% EE) for further conjugation with CTX. The high cytotoxicity of CHC-loaded NPs and conjugated NPs was evidenced for different glioma cell lines (U251 and SW1088). A chicken chorioallantoic membrane assay highlighted the expressive antiangiogenic activity of CHC-loaded NPs, which was enhanced for conjugated NPs. The findings of this work demonstrated the potential of this nanostructured polymeric platform to become a novel therapeutic alternative for GBM treatment.

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Acknowledgments

The authors would like to thank the National Institute of Science and Technology in Pharmaceutical Nanotechnology: a transdisciplinary approach INCT-NANOFARMA, which is supported by the “Fundação de Amparo e Pesquisa do Estado de São Paulo” (FAPESP, Brazil), Grant #2014/50928-2, and by “Conselho Nacional de Desenvolvimento Científico e Tecnológico” (CNPq, Brazil), Grant # 465687/2014-8.

Funding

This work was financially supported by FAPESP Grant # 2017/16324-0. NNF received fellowships from FAPESP, ref. #2016/09671-3 and #2018/ 04546-1. This work has been funded through the Foundation for Science and Technology (FCT) - project UIDB/50026/2020 and UIDP/50026/2020; and by the projects NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). SG received a fellowship from FCT, ref. SFRH/BPD/117858/2016.

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Authors and Affiliations

  1. School of Pharmaceutical Science, São Paulo State University, UNESP, Rodovia Araraquara/Jaú Km 01, Araraquara, São Paulo, 14801-902, Brazil

    Natália N. Ferreira, Fernanda I. Boni, Fabíola G. Prezotti, Leonardo M. B. Ferreira, Beatriz S. F. Cury & Maria Palmira D. Gremião

  2. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

    Sara Granja, Rui M. Reis & Fátima Baltazar

  3. ICVS/3B’s-PT Government Associate Laboratory, Braga, Guimarães, Portugal

    Sara Granja, Rui M. Reis & Fátima Baltazar

  4. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil

    Rui M. Reis

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  1. Natália N. Ferreira
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  7. Rui M. Reis
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  8. Fátima Baltazar
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  9. Maria Palmira D. Gremião
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Contributions

Conceptualization, methodology, and data acquisition: N.N.F., S.G., L.M.B.F., F.G.P., F.I.B. B.S.F.C; resources: M.P.D.G., F.B., R.M.R.; data curation: all authors; writing of original draft: N.N.F., B.S.F.C., F.G.P., F.I.B. L.M.B.F.; writing review and editing: all authors; supervision: M.P.D.G., B.S.F.C., F.B., R.M.R. project administration and funding acquisition: M.P.D.G., F.B.; data analysis and scientific discussion: all authors.

Corresponding author

Correspondence to Maria Palmira D. Gremião.

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Ferreira, N.N., Granja, S., Boni, F.I. et al. Modulating chitosan-PLGA nanoparticle properties to design a co-delivery platform for glioblastoma therapy intended for nose-to-brain route. Drug Deliv. and Transl. Res. 10, 1729–1747 (2020). https://doi.org/10.1007/s13346-020-00824-2

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