Vol.:(0123456789) 1 3 Drug Delivery and Translational Research https://doi.org/10.1007/s13346-021-00917-6 ORIGINAL ARTICLE Quercetin‑biapigenin nanoparticles are efective to penetrate the blood–brain barrier Ana Isabel Oliveira 1  · Cláudia Pinho 1  · Bruno Sarmento 2,3,4  · Alberto C. P. Dias 5 Accepted: 18 January 2021 © Controlled Release Society 2021 Abstract Search for efcient therapeutic agents for central nervous system (CNS) disorders has been extensive. Nevertheless, blood– brain barrier (BBB) is an obstacle that prevents the majority of compounds to act in these diseases. It is, thus, of extreme relevance the BBB overcome, in order to deliver a drugs therapeutically active concentration to the action site, with the least losses and interaction with other organs, tissues, or cells. The present study aimed to investigate the potential protective efect of quercetin-biapigenin encapsulated into poly(Ɛ-polycaprolactone) (PCL) nanoparticles against t -BOOH-induced oxidative stress in several brain cell lines, as well as evaluate the permeability of those active molecules through an in vitro BBB model. The three cell lines under study (BV-2, hcmec/D3, and U87) presented diferent reactions to t-BOOH. In general, quercetin-biapigenin PCL-loaded nanoparticles were able to minimize compound toxicity they convey, regardless the cell line. Quercetin-biapigenin PCL-loaded nanoparticles (Papp of approximately 80 × 10–6 cm/s) revealed to be more permeable than free compounds (Papp of approximately 50 × 10–6 cm/s). As of our knowledge, this is the frst report of quercetin-biapigenin PCL-loaded nanoparticle activity in brain cells. It is also the frst determining its permeability through BBB, as an efective nanocarrier for brain delivery Keywords Quercetin · Biapigenin · Poly(ɛ-polycaprolactone) · Nanoparticles · Neuroprotection · Permeability Introduction One of the main debilitating diseases of the twenty-first century is neurodegenerative disorder. Its rapid increase over the last decades is related with the increase of life expectance, as age is considered the biggest risk factor in most neurodegenerative diseases. Moreover, oxidative stress increases in brain during aging [1, 2]. Dependent of anatomical and physiological characteristics, central nervous system (CNS) is known to be especially sensitive to oxidative stress. This is due to several factors, as high O 2 consumption—the human brain accounts for a small percentage of the body weight. However, it processes 20% of basal O 2 consumption. The brain also possesses high content of iron and ascorbate, which are directly related to lipid peroxidation and high content of easily peroxidizable unsaturated fatty acids (especially 20:4 and 22:6 fatty acids). Also, the brain does not possess high levels of protective defenses, namely antioxidants [1, 3]. The brain possesses its own sources of oxidative stress, namely the excitatory amino acids and neurotransmitters whose metabolism lead to the production of reactive oxygen species (ROS). Other sources are generated by the high and constant use of oxygen by the mitochondria. ROS are also produced by CYP450 electron transport and monoamine oxidase activity [4]. The maintenance of redox environment and cell mitochondrial function are, therefore, essential. This * Ana Isabel Oliveira aio@ess.ipp.pt; aio@estsp.ipp.pt 1 Centro de Investigação Em Saúde E Ambiente (CISA), Escola Superior de Saúde –Politécnico do Porto (ESS-P. Porto), 4000-072 Porto, Portugal 2 i3S - Instituto de Investigação E Inovação Em Saúde, Universidade Do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal 3 INEB - Instituto Nacional de Engenharia Biomédica, Universidade Do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal 4 CESPU, Instituto de Investigação E Formação Avançada Em Ciências E Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, 4585-116 Gandra, Portugal 5 Centre of Molecular and Environmental Biology (CBMA), Biology Department, Department of Biology, University of Minho, 4710-057 Braga, Portugal