Design, synthesis, and biological evaluation of cathepsin B cleavage albumin-binding SN38 prodrug in breast cancer.
Bioorg Chem
; 147: 107370, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38621338
ABSTRACT
Here, we introduce a novel and effective approach utilizing a cathepsin B cleavage albumin-binding SN38 prodrug specifically designed for the treatment of metastatic breast cancer. Termed Mal-va-mac-SN38, our prodrug exhibits a unique ability to rapidly and covalently bind with endogenous albumin, resulting in the formation of HSA-va-mac-SN38. This prodrug demonstrates exceptional stability in human plasma. Importantly, HSA-va-mac-SN38 showcases an impressive enhancement in cellular uptake by 4T1 breast cancer cells, primarily facilitated through caveolin-mediated endocytosis. Intriguingly, the release of the active SN38, is triggered by the enzymatic activity of cathepsin B within the lysosomal environment. In vivo studies employing a lung metastasis 4T1 breast cancer model underscore the potency of HSA-va-mac-SN38. Histological immunohistochemical analyses further illuminate the multifaceted impact of our prodrug, showcasing elevated levels of apoptosis, downregulated expression of matrix metalloproteinases, and inhibition of angiogenesis, all critical factors contributing to the anti-metastatic effect observed. Biodistribution studies elucidate the capacity of Mal-va-mac-SN38 to augment tumor accumulation through covalent binding to serum albumin, presenting a potential avenue for targeted therapeutic interventions. Collectively, our findings propose a promising therapeutic avenue for metastatic breast cancer, through the utilization of a cathepsin B-cleavable albumin-binding prodrug.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
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Pró-Fármacos
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Catepsina B
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Desenho de Fármacos
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Antineoplásicos
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2024
Tipo de documento:
Article