Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-01-01
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| Series: | Biomedicine & Pharmacotherapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S075333222201410X |
| _version_ | 1811179071768363008 |
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| author | Jacinta O. Pinho Mariana Matias Vanda Marques Carla Eleutério Célia Fernandes Lurdes Gano Joana D. Amaral Eduarda Mendes Maria Jesus Perry João Nuno Moreira Gert Storm Ana Paula Francisco Cecília M.P. Rodrigues M. Manuela Gaspar |
| author_facet | Jacinta O. Pinho Mariana Matias Vanda Marques Carla Eleutério Célia Fernandes Lurdes Gano Joana D. Amaral Eduarda Mendes Maria Jesus Perry João Nuno Moreira Gert Storm Ana Paula Francisco Cecília M.P. Rodrigues M. Manuela Gaspar |
| author_sort | Jacinta O. Pinho |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T06:28:23Z |
| format | Article |
| id | doaj.art-8bcb887236f344f381f68daa3c7e19f5 |
| institution | Directory Open Access Journal |
| issn | 0753-3322 |
| language | English |
| last_indexed | 2024-04-11T06:28:23Z |
| publishDate | 2023-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Biomedicine & Pharmacotherapy |
| spelling | doaj.art-8bcb887236f344f381f68daa3c7e19f52022-12-22T04:40:15ZengElsevierBiomedicine & Pharmacotherapy0753-33222023-01-01157114021Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma managementJacinta O. Pinho0Mariana Matias1Vanda Marques2Carla Eleutério3Célia Fernandes4Lurdes Gano5Joana D. Amaral6Eduarda Mendes7Maria Jesus Perry8João Nuno Moreira9Gert Storm10Ana Paula Francisco11Cecília M.P. Rodrigues12M. Manuela Gaspar13Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalCentro de Ciências e Tecnologias Nucleares and Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Bobadela LRS, PortugalCentro de Ciências e Tecnologias Nucleares and Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Bobadela LRS, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalCenter for Neurosciences and Cell Biology (CNC), Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Faculty of Medicine (Polo 1), Rua Larga, 3004-504 Coimbra, Portugal; University of Coimbra (Univ Coimbra), CIBB, Faculty of Pharmacy, Pólo das Ciências da Saúde, Azinhaga de Santa Comba, 3000-548 Coimbra, PortugalDepartment of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands; Department of Biomaterial Science and Technology, University of Twente, Enschede, the Netherlands; Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, SingaporeResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, PortugalResearch Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S075333222201410XHybrid moleculesLiposomesMelanomaIn vitro studiesMelanoma murine modelsPreclinical studies |
| spellingShingle | Jacinta O. Pinho Mariana Matias Vanda Marques Carla Eleutério Célia Fernandes Lurdes Gano Joana D. Amaral Eduarda Mendes Maria Jesus Perry João Nuno Moreira Gert Storm Ana Paula Francisco Cecília M.P. Rodrigues M. Manuela Gaspar Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management Biomedicine & Pharmacotherapy Hybrid molecules Liposomes Melanoma In vitro studies Melanoma murine models Preclinical studies |
| title | Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management |
| title_full | Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management |
| title_fullStr | Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management |
| title_full_unstemmed | Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management |
| title_short | Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management |
| title_sort | preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management |
| topic | Hybrid molecules Liposomes Melanoma In vitro studies Melanoma murine models Preclinical studies |
| url | http://www.sciencedirect.com/science/article/pii/S075333222201410X |
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