PAMAM dendrimers: blood-brain barrier transport and neuronal uptake after focal brain ischemia
| Autor: | Sofia Duque Santos, Miguel Xavier, Helena Tomás, Marília Torrado, Rita Castro, João Rodrigues, Ana Paula Pêgo, Victoria Leiro, Beatriz Custódio, Débora A. Moreira, Diana Moreira Leite |
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| Přispěvatelé: | Instituto de Investigação e Inovação em Saúde |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Pharmaceutical Science 02 engineering and technology Brain Ischemia Polyethylene Glycols Brain ischemia Drug Delivery Systems Cells Cultured Blood-brain barrier Drug Carriers Chemistry 021001 nanoscience & nanotechnology Haemolysis 3. Good health Stroke Nanomedicine medicine.anatomical_structure Blood-Brain Barrier Drug delivery 0210 nano-technology Dendrimers Context (language use) Blood–brain barrier Brainischemia Cell Line Faculdade de Ciências Exatas e da Engenharia 03 medical and health sciences In vivo In-vivo Dendrimer Poly(ethyleneglycol) PEG medicine Animals Humans Rats Wistar Dendrimers Poly(amidoamine) PAMAM Nanomaterials Biological Transport medicine.disease Poly(amido amine) Blood-brainbarrier Mice Inbred C57BL 030104 developmental biology Astrocytes PEGylation Biophysics |
| Zdroj: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP |
| Popis: | Drug delivery to the central nervous system is restricted by the blood-brain barrier (BBB). However, with the onset of stroke, the BBB becomes leaky, providing a window of opportunity to passively target the brain. Here, cationic poly(amido amine) (PAMAM) dendrimers of different generations were functionalized with poly(ethylene glycol) (PEG) to reduce cytotoxicity and prolong blood circulation half-life, aiming for a safe in vivo drug delivery system in a stroke scenario. Rhodamine B isothiocyanate (RITC) was covalently tethered to the dendrimer backbone and used as a small surrogate drug as well as for tracking purposes. The biocompatibility of PAMAM was markedly increased by PEGylation as a function of dendrimer generation and degree of functionalization. The PEGylated RITC-modified dendrimers did not affect the integrity of an in vitro BBB model. Additionally, the functionalized dendrimers remained safe when in contact with the bEnd.3 cells and rat primary astrocytes composing the in vitro BBB model after hypoxia induced by oxygen-glucose deprivation. Modification with PEG also decreased the interaction and uptake by endothelial cells of PAMAM, indicating that the transport across a leaky BBB due to focal brain ischemia would be facilitated. Next, the functionalized dendrimers were tested in contact with red blood cells showing no haemolysis for the PEGylated PAMAM, in contrast to the unmodified dendrimer. Interestingly, the PEG-modified dendrimers reduced blood clotting, which may be an added beneficial function in the context of stroke. The optimized PAMAM formulation was intravenously administered in mice after inducing permanent focal brain ischemia. Twenty-four hours after administration, dendrimers could be detected in the brain, including in neurons of the ischemic cortex. Our results suggest that the proposed formulation has the potential for becoming a successful delivery vector for therapeutic application to the injured brain after stroke reaching the ischemic neurons. The authors acknowledge the financial support of the Fundo para a Investigação em Saúde (INFARMED, project reference FIS-2015-01_CCV_20150630-88), as well as the FEDER funds (NORTE-01-0145-FEDER-000008) through the Programa Operacional Competitividade e Internacionalização - COMPETE 2020 and the Portuguese funds through FCT – Fundação para a Ciência e a Tecnologia in the frame of the projects (PTDC/CTM-NAN/112428/2009 and PTDC/CTM-NAN/3547/2014). Acknowledgements are also due to FCT by the grant PEst-OE/QUI/UI0674/2013 (CQM, Portuguese government). Funding through the project Centro de Química da Madeira – CQM + (M1420-01-0145-FEDER-000005, ARDITI) by Madeira Regional Operational Programme (Madeira 1420) is also acknowledged. S.D. Santos acknowledges the support by FCT for the post-doctoral fellowship (SFRH/BPD/109297/2015). V. Leiro acknowledges the support by the project NORTE-01-0145-FEDER-000012, financed by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). The authors would also like to acknowledge Frederico Silva (Biochemical and Biophysical Technologies – b2Tech) Rui Fernandes (Histology and Electron Microscopy - HEMS), Sofia Lamas (i3S Animal Facility), Paula Magalhães (Cell Culture and Genotyping - CCGen) and Maria Lazaro (Bioimaging) for the support at i3S Scientific Platforms. The authors acknowledge Centro de Materiais da Universidade do Porto (CEMUP) for NMR analysis. Appendix A |
| Databáze: | OpenAIRE |
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