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Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I
Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor wa...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698893/ https://www.ncbi.nlm.nih.gov/pubmed/33218172 http://dx.doi.org/10.3390/pharmaceutics12111110 |
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author | Shkodra, Blerina Press, Adrian T. Vollrath, Antje Nischang, Ivo Schubert, Stephanie Hoeppener, Stephanie Haas, Dorothee Enzensperger, Christoph Lehmann, Marc Babic, Petra Benecke, Kay Jovana Traeger, Anja Bauer, Michael Schubert, Ulrich S. |
author_facet | Shkodra, Blerina Press, Adrian T. Vollrath, Antje Nischang, Ivo Schubert, Stephanie Hoeppener, Stephanie Haas, Dorothee Enzensperger, Christoph Lehmann, Marc Babic, Petra Benecke, Kay Jovana Traeger, Anja Bauer, Michael Schubert, Ulrich S. |
author_sort | Shkodra, Blerina |
collection | PubMed |
description | Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic-co-glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations. |
format | Online Article Text |
id | pubmed-7698893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76988932020-11-29 Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I Shkodra, Blerina Press, Adrian T. Vollrath, Antje Nischang, Ivo Schubert, Stephanie Hoeppener, Stephanie Haas, Dorothee Enzensperger, Christoph Lehmann, Marc Babic, Petra Benecke, Kay Jovana Traeger, Anja Bauer, Michael Schubert, Ulrich S. Pharmaceutics Article Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic-co-glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations. MDPI 2020-11-18 /pmc/articles/PMC7698893/ /pubmed/33218172 http://dx.doi.org/10.3390/pharmaceutics12111110 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Shkodra, Blerina Press, Adrian T. Vollrath, Antje Nischang, Ivo Schubert, Stephanie Hoeppener, Stephanie Haas, Dorothee Enzensperger, Christoph Lehmann, Marc Babic, Petra Benecke, Kay Jovana Traeger, Anja Bauer, Michael Schubert, Ulrich S. Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I |
title | Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I |
title_full | Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I |
title_fullStr | Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I |
title_full_unstemmed | Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I |
title_short | Formulation of Liver-Specific PLGA-DY-635 Nanoparticles Loaded with the Protein Kinase C Inhibitor Bisindolylmaleimide I |
title_sort | formulation of liver-specific plga-dy-635 nanoparticles loaded with the protein kinase c inhibitor bisindolylmaleimide i |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698893/ https://www.ncbi.nlm.nih.gov/pubmed/33218172 http://dx.doi.org/10.3390/pharmaceutics12111110 |
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