Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management
Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved..
The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma. HM displayed remarkable superior antiproliferative activity towards various cancer cell lines compared with temozolomide (TMZ), a triazene drug in clinical use, that acts through DNA alkylation. In B16-F10 cells, HM induced a cell cycle arrest at phase G0/G1 with a 2.8-fold decrease in cell proliferation index. Also, compared to control cells, HM led to a concentration-dependent reduction in tyrosinase activity and increase in caspase 3/7 activity. To maximize the therapeutic performance of HM in vivo, its incorporation in long blood circulating liposomes, containing poly(ethylene glycol) (PEG) at their surface, was performed for passively targeting tumour sites. HM liposomes (LIP HM) exhibited high stability in biological fluids. Preclinical studies demonstrated its safety for systemic administration and in a subcutaneous murine melanoma model, significantly reduced tumour progression. In a metastatic murine melanoma model, a superior antitumour effect was also observed for mice receiving LIP HM, with markedly reduction of lung metastases compared to positive control group (TMZ). Biodistribution studies using 111In-labelled LIP HM demonstrated its ability for passively targeting tumour sites, thus correlating with the high therapeutic effect observed in the two experimental murine melanoma models. Overall, our proposed nanotherapeutic strategy was validated as an effective and safe alternative against melanoma.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:157 |
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| Enthalten in: |
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie - 157(2023) vom: 15. Jan., Seite 114021 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pinho, Jacinta O [VerfasserIn] |
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| Links: |
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| Themen: |
Hybrid molecules |
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| Anmerkungen: |
Date Completed 16.12.2022 Date Revised 21.12.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.biopha.2022.114021 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved. | ||
| 520 | |a The aggressiveness of melanoma and lack of effective therapies incite the discovery of novel strategies. Recently, a new dual acting hybrid molecule (HM), combining a triazene and a ʟ-tyrosine analogue, was synthesized. HM was designed to specifically be activated by tyrosinase, the enzyme involved in melanin biosynthesis and overexpressed in melanoma. HM displayed remarkable superior antiproliferative activity towards various cancer cell lines compared with temozolomide (TMZ), a triazene drug in clinical use, that acts through DNA alkylation. In B16-F10 cells, HM induced a cell cycle arrest at phase G0/G1 with a 2.8-fold decrease in cell proliferation index. Also, compared to control cells, HM led to a concentration-dependent reduction in tyrosinase activity and increase in caspase 3/7 activity. To maximize the therapeutic performance of HM in vivo, its incorporation in long blood circulating liposomes, containing poly(ethylene glycol) (PEG) at their surface, was performed for passively targeting tumour sites. HM liposomes (LIP HM) exhibited high stability in biological fluids. Preclinical studies demonstrated its safety for systemic administration and in a subcutaneous murine melanoma model, significantly reduced tumour progression. In a metastatic murine melanoma model, a superior antitumour effect was also observed for mice receiving LIP HM, with markedly reduction of lung metastases compared to positive control group (TMZ). Biodistribution studies using 111In-labelled LIP HM demonstrated its ability for passively targeting tumour sites, thus correlating with the high therapeutic effect observed in the two experimental murine melanoma models. Overall, our proposed nanotherapeutic strategy was validated as an effective and safe alternative against melanoma | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Hybrid molecules | |
| 650 | 4 | |a In vitro studies | |
| 650 | 4 | |a Liposomes | |
| 650 | 4 | |a Melanoma | |
| 650 | 4 | |a Melanoma murine models | |
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| 700 | 1 | |a Fernandes, Célia |e verfasserin |4 aut | |
| 700 | 1 | |a Gano, Lurdes |e verfasserin |4 aut | |
| 700 | 1 | |a Amaral, Joana D |e verfasserin |4 aut | |
| 700 | 1 | |a Mendes, Eduarda |e verfasserin |4 aut | |
| 700 | 1 | |a Perry, Maria Jesus |e verfasserin |4 aut | |
| 700 | 1 | |a Moreira, João Nuno |e verfasserin |4 aut | |
| 700 | 1 | |a Storm, Gert |e verfasserin |4 aut | |
| 700 | 1 | |a Francisco, Ana Paula |e verfasserin |4 aut | |
| 700 | 1 | |a Rodrigues, Cecília M P |e verfasserin |4 aut | |
| 700 | 1 | |a Gaspar, M Manuela |e verfasserin |4 aut | |
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