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Targeting cancer cells in acidosis with conjugates between the carnitine palmitoyltransferase 1 inhibitor etomoxir and pH (low) insertion peptides.
- Source :
-
International journal of pharmaceutics [Int J Pharm] 2022 Aug 25; Vol. 624, pp. 122041. Date of Electronic Publication: 2022 Jul 20. - Publication Year :
- 2022
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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.<br /> (Copyright © 2022 Elsevier B.V. All rights reserved.)
Details
- Language :
- English
- ISSN :
- 1873-3476
- Volume :
- 624
- Database :
- MEDLINE
- Journal :
- International journal of pharmaceutics
- Publication Type :
- Academic Journal
- Accession number :
- 35868479
- Full Text :
- https://doi.org/10.1016/j.ijpharm.2022.122041