Targeting cancer cells in acidosis with conjugates between the carnitine palmitoyltransferase 1 inhibitor etomoxir and pH (low) insertion peptides.
Int J Pharm
; 624: 122041, 2022 Aug 25.
Article
em En
| MEDLINE
| ID: mdl-35868479
ABSTRACT
Targeting enzymes involved in tumor metabolism is a promising way to tackle cancer progression. The inhibition of carnitine palmitoyltransferase 1 (CPT1) by etomoxir (Eto) efficiently slows down the growth of various cancers. Unfortunately, the clinical use of this drug was abandoned because of hepatotoxic effects. We report the development of pH-sensitive peptide (pHLIP)-drug conjugate to deliver Eto selectively to cancer cells exposed to acidic microenvironmental conditions. A newly designed sequence for the pHLIP peptide, named pHLIPd, was compared with a previously published reference pHLIP peptide, named pHLIPr. We showed that the conjugate between pHLIPd and Eto has a better pH-dependent insertion and structuration than the pHLIPr-based conjugate inside POPC vesicles. We observed antiproliferative effects when applied on acid-adapted cancer cells, reaching a larger inhibitory activity than Eto alone. In conclusion, this study brings the first evidence that pHLIP-based conjugates with a CPT1 inhibitor has the potential to specifically target the tumor acidic compartment and exert anticancer effects while sparing healthy tissues.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Acidose
/
Neoplasias
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article