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Title: Preclinical validation of a new hybrid molecule loaded in liposomes for melanoma management
Authors: Pinho, Jacinta O.
Matias, Mariana
Marques, Vanda
Eleutério, Carla
Fernandes, Célia 
Gano, Lurdes
Amaral, Joana D.
Mendes, Eduarda
Perry, Maria Jesus
Moreira, João Nuno 
Storm, Gert
Francisco, Ana Paula
Rodrigues, Cecília M. P.
Gaspar, M Manuela
Keywords: Hybrid molecules; Liposomes; Melanoma; In vitro studies; Melanoma murine models; Preclinical studies
Issue Date: Jan-2023
Publisher: Elsevier
Project: The Phospholipid Research Center is kindly acknowledged for the financial support Grant number: MMG-2021-092/1 -1. 
PTDC/ MED-QUI/31721/2017 
PhD grant SFRH/BD/117586/2016 
Serial title, monograph or event: Biomedicine and Pharmacotherapy
Volume: 157
Abstract: 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.
ISSN: 07533322
DOI: 10.1016/j.biopha.2022.114021
Rights: openAccess
Appears in Collections:FFUC- Artigos em Revistas Internacionais
I&D CIBB - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais
FMUC Medicina - Artigos em Revistas Internacionais

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