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The article discusses the development of a glutathione-activated prodrug of Pimasertib for targeted cancer therapy. The prodrug, called PROPIMA, contains a redox-sensitive linker that can be activated by glutathione to release the active drug. The study demonstrates that PROPIMA, whether free or loaded in liposomes, selectively inhibits melanoma cell proliferation and viability, reduces pERK levels, and shows stronger inhibition of cancer cell migration compared to the parent drug. This research highlights the potential of using prodrugs in combination with nanodelivery systems for improved cancer treatment.
Pimasertib, a potent antiproliferative drug, has been extensively studied for the treatment of cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would greatly benefit from an increased selectivity for tumour cells and a longer half-life. Such improvements may be achieved through the combination of the rational design of a prodrug with its encapsulation in a potential nanodelivery system. For this reason, we synthetized a glutathione (GSH)-responsive putative prodrug of Pimasertib (PROPIMA), which contains a redox-sensitive disulphide linker that can be processed by GSH to active Pimasertib. The synthesis of PROPIMA is described, as is its in vitro biological activity on a human melanoma cell line as a model. The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing of about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration in comparison to the parent drug.
This article is Open Access
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