Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery System
Zuzana Skubalova,1,2 Simona Rex,1,2 Martina Sukupova,1 Martin Zahalka,1 Petr Skladal,3 Jan Pribyl,3 Hana Michalkova,1,2 Akila Weerasekera,4 Vojtech Adam,1,2 Zbynek Heger1,2 1Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic; 2Central European Institute of Tech...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2021-01-01
|
| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/passive-diffusion-vs-active-ph-dependent-encapsulation-of-tyrosine-kin-peer-reviewed-article-IJN |
| _version_ | 1819202787676782592 |
|---|---|
| author | Skubalova Z Rex S Sukupova M Zahalka M Skladal P Pribyl J Michalkova H Weerasekera A Adam V Heger Z |
| author_facet | Skubalova Z Rex S Sukupova M Zahalka M Skladal P Pribyl J Michalkova H Weerasekera A Adam V Heger Z |
| author_sort | Skubalova Z |
| collection | DOAJ |
| description | Zuzana Skubalova,1,2 Simona Rex,1,2 Martina Sukupova,1 Martin Zahalka,1 Petr Skladal,3 Jan Pribyl,3 Hana Michalkova,1,2 Akila Weerasekera,4 Vojtech Adam,1,2 Zbynek Heger1,2 1Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic; 2Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic; 3Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 4Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USACorrespondence: Zbynek HegerDepartment of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, Brno CZ-613 00, Czech RepublicTel +420-5-4513-3350Fax +420-5-4521-2044Email heger@mendelu.czIntroduction: The present study reports on examination of the effects of encapsulating the tyrosine kinase inhibitors (TKIs) vandetanib and lenvatinib into a biomacromolecular ferritin-based delivery system.Methods: The encapsulation of TKIs was performed via two strategies: i) using an active reversible pH-dependent reassembly of ferritin´s quaternary structure and ii) passive loading of hydrophobic TKIs through the hydrophobic channels at the junctions of ferritin subunits. After encapsulation, ferritins were surface-functionalized with folic acid promoting active-targeting capabilities.Results: The physico-chemical and nanomechanical analyses revealed that despite the comparable encapsulation efficiencies of both protocols, the active loading affects stability and rigidity of ferritins, plausibly due to their imperfect reassembly. Biological experiments with hormone-responsive breast cancer cells (T47-D and MCF-7) confirmed the cytotoxicity of encapsulated and folate-targeted TKIs to folate-receptor positive cancer cells, but only limited cytotoxic effects to healthy breast epithelium. Importantly, the long-term cytotoxic experiments revealed that compared to the pH-dependent encapsulation, the passively-loaded TKIs exert markedly higher anticancer activity, most likely due to undesired influence of harsh acidic environment used for the pH-dependent encapsulation on the TKIs’ structural and functional properties.Conclusion: Since the passive loading does not require a reassembly step for which acids are needed, the presented investigation serves as a solid basis for future studies focused on encapsulation of small hydrophobic molecules.Keywords: drug delivery, nanomedicine, lenvatinib, vandetanib |
| first_indexed | 2024-12-23T04:09:34Z |
| format | Article |
| id | doaj.art-9696b6f0dd2846acb00866412d6aad4f |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-23T04:09:34Z |
| publishDate | 2021-01-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-9696b6f0dd2846acb00866412d6aad4f2022-12-21T18:00:33ZengDove Medical PressInternational Journal of Nanomedicine1178-20132021-01-01Volume 1611460908Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery SystemSkubalova ZRex SSukupova MZahalka MSkladal PPribyl JMichalkova HWeerasekera AAdam VHeger ZZuzana Skubalova,1,2 Simona Rex,1,2 Martina Sukupova,1 Martin Zahalka,1 Petr Skladal,3 Jan Pribyl,3 Hana Michalkova,1,2 Akila Weerasekera,4 Vojtech Adam,1,2 Zbynek Heger1,2 1Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic; 2Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic; 3Central European Institute of Technology, Masaryk University, Brno, Czech Republic; 4Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USACorrespondence: Zbynek HegerDepartment of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, Brno CZ-613 00, Czech RepublicTel +420-5-4513-3350Fax +420-5-4521-2044Email heger@mendelu.czIntroduction: The present study reports on examination of the effects of encapsulating the tyrosine kinase inhibitors (TKIs) vandetanib and lenvatinib into a biomacromolecular ferritin-based delivery system.Methods: The encapsulation of TKIs was performed via two strategies: i) using an active reversible pH-dependent reassembly of ferritin´s quaternary structure and ii) passive loading of hydrophobic TKIs through the hydrophobic channels at the junctions of ferritin subunits. After encapsulation, ferritins were surface-functionalized with folic acid promoting active-targeting capabilities.Results: The physico-chemical and nanomechanical analyses revealed that despite the comparable encapsulation efficiencies of both protocols, the active loading affects stability and rigidity of ferritins, plausibly due to their imperfect reassembly. Biological experiments with hormone-responsive breast cancer cells (T47-D and MCF-7) confirmed the cytotoxicity of encapsulated and folate-targeted TKIs to folate-receptor positive cancer cells, but only limited cytotoxic effects to healthy breast epithelium. Importantly, the long-term cytotoxic experiments revealed that compared to the pH-dependent encapsulation, the passively-loaded TKIs exert markedly higher anticancer activity, most likely due to undesired influence of harsh acidic environment used for the pH-dependent encapsulation on the TKIs’ structural and functional properties.Conclusion: Since the passive loading does not require a reassembly step for which acids are needed, the presented investigation serves as a solid basis for future studies focused on encapsulation of small hydrophobic molecules.Keywords: drug delivery, nanomedicine, lenvatinib, vandetanibhttps://www.dovepress.com/passive-diffusion-vs-active-ph-dependent-encapsulation-of-tyrosine-kin-peer-reviewed-article-IJNdrug deliverynanomedicinelenvatinibvandetanib |
| spellingShingle | Skubalova Z Rex S Sukupova M Zahalka M Skladal P Pribyl J Michalkova H Weerasekera A Adam V Heger Z Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery System International Journal of Nanomedicine drug delivery nanomedicine lenvatinib vandetanib |
| title | Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery System |
| title_full | Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery System |
| title_fullStr | Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery System |
| title_full_unstemmed | Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery System |
| title_short | Passive Diffusion vs Active pH-Dependent Encapsulation of Tyrosine Kinase Inhibitors Vandetanib and Lenvatinib into Folate-Targeted Ferritin Delivery System |
| title_sort | passive diffusion vs active ph dependent encapsulation of tyrosine kinase inhibitors vandetanib and lenvatinib into folate targeted ferritin delivery system |
| topic | drug delivery nanomedicine lenvatinib vandetanib |
| url | https://www.dovepress.com/passive-diffusion-vs-active-ph-dependent-encapsulation-of-tyrosine-kin-peer-reviewed-article-IJN |
| work_keys_str_mv | AT skubalovaz passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT rexs passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT sukupovam passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT zahalkam passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT skladalp passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT pribylj passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT michalkovah passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT weerasekeraa passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT adamv passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem AT hegerz passivediffusionvsactivephdependentencapsulationoftyrosinekinaseinhibitorsvandetanibandlenvatinibintofolatetargetedferritindeliverysystem |