Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin
Abstract Strategies targeting nucleolin have enabled a significant improvement in intracellular bioavailability of their encapsulated payloads. In this respect, assessment of the impact of target cell heterogeneity and nucleolin homology across species (structurally and functionally)...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer US
2022
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| Online Access: | https://hdl.handle.net/1721.1/139779 |
| _version_ | 1811078955691671552 |
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| author | Lopes, Rui Shi, Kevin Fonseca, Nuno A. Gama, Adelina Ramalho, José S. Almeida, Luís Moura, Vera Simões, Sérgio Tidor, Bruce Moreira, João N. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Lopes, Rui Shi, Kevin Fonseca, Nuno A. Gama, Adelina Ramalho, José S. Almeida, Luís Moura, Vera Simões, Sérgio Tidor, Bruce Moreira, João N. |
| author_sort | Lopes, Rui |
| collection | MIT |
| description | Abstract
Strategies targeting nucleolin have enabled a significant improvement in intracellular bioavailability of their encapsulated payloads. In this respect, assessment of the impact of target cell heterogeneity and nucleolin homology across species (structurally and functionally) is of major importance. This work also aimed at mathematically modelling the nucleolin expression levels at the cell membrane, binding and internalization of pH-sensitive pegylated liposomes encapsulating doxorubicin and functionalized with the nucleolin-binding F3 peptide (PEGASEMP), and resulting cytotoxicity against cancer cells from mouse, rat, canine, and human origin. Herein, it was shown that nucleolin expression levels were not a limitation on the continuous internalization of F3 peptide-targeted liposomes, despite the saturable nature of the binding mechanism. Modeling enabled the prediction of nucleolin-mediated total doxorubicin exposure provided by the experimental settings of the assessment of PEGASEMP’s impact on cell death. The former increased proportionally with nucleolin-binding sites, a measure relevant for patient stratification. This pattern of variation was observed for the resulting cell death in nonsaturating conditions, depending on the cancer cell sensitivity to doxorubicin. This approach differs from standard determination of cytotoxic concentrations, which normally report values of incubation doses rather than the actual intracellular bioactive drug exposure. Importantly, in the context of development of nucleolin-based targeted drug delivery, the structural nucleolin homology (higher than 84%) and functional similarity across species presented herein, emphasized the potential to use toxicological data and other metrics from lower species to infer the dose for a first-in-human trial.
Graphical abstract |
| first_indexed | 2024-09-23T11:07:53Z |
| format | Article |
| id | mit-1721.1/139779 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T11:07:53Z |
| publishDate | 2022 |
| publisher | Springer US |
| record_format | dspace |
| spelling | mit-1721.1/1397792023-04-11T20:18:19Z Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin Lopes, Rui Shi, Kevin Fonseca, Nuno A. Gama, Adelina Ramalho, José S. Almeida, Luís Moura, Vera Simões, Sérgio Tidor, Bruce Moreira, João N. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Abstract Strategies targeting nucleolin have enabled a significant improvement in intracellular bioavailability of their encapsulated payloads. In this respect, assessment of the impact of target cell heterogeneity and nucleolin homology across species (structurally and functionally) is of major importance. This work also aimed at mathematically modelling the nucleolin expression levels at the cell membrane, binding and internalization of pH-sensitive pegylated liposomes encapsulating doxorubicin and functionalized with the nucleolin-binding F3 peptide (PEGASEMP), and resulting cytotoxicity against cancer cells from mouse, rat, canine, and human origin. Herein, it was shown that nucleolin expression levels were not a limitation on the continuous internalization of F3 peptide-targeted liposomes, despite the saturable nature of the binding mechanism. Modeling enabled the prediction of nucleolin-mediated total doxorubicin exposure provided by the experimental settings of the assessment of PEGASEMP’s impact on cell death. The former increased proportionally with nucleolin-binding sites, a measure relevant for patient stratification. This pattern of variation was observed for the resulting cell death in nonsaturating conditions, depending on the cancer cell sensitivity to doxorubicin. This approach differs from standard determination of cytotoxic concentrations, which normally report values of incubation doses rather than the actual intracellular bioactive drug exposure. Importantly, in the context of development of nucleolin-based targeted drug delivery, the structural nucleolin homology (higher than 84%) and functional similarity across species presented herein, emphasized the potential to use toxicological data and other metrics from lower species to infer the dose for a first-in-human trial. Graphical abstract 2022-01-28T12:49:21Z 2022-01-28T12:49:21Z 2021-04-15 2022-01-28T04:27:02Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/139779 Lopes, Rui, Shi, Kevin, Fonseca, Nuno A., Gama, Adelina, Ramalho, José S. et al. 2021. "Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin." en https://doi.org/10.1007/s13346-021-00972-z Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ Controlled Release Society application/pdf Springer US Springer US |
| spellingShingle | Lopes, Rui Shi, Kevin Fonseca, Nuno A. Gama, Adelina Ramalho, José S. Almeida, Luís Moura, Vera Simões, Sérgio Tidor, Bruce Moreira, João N. Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin |
| title | Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin |
| title_full | Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin |
| title_fullStr | Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin |
| title_full_unstemmed | Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin |
| title_short | Modelling the impact of nucleolin expression level on the activity of F3 peptide-targeted pH-sensitive pegylated liposomes containing doxorubicin |
| title_sort | modelling the impact of nucleolin expression level on the activity of f3 peptide targeted ph sensitive pegylated liposomes containing doxorubicin |
| url | https://hdl.handle.net/1721.1/139779 |
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