Esomeprazole

Proton pump inhibitors (PPIs) act on the final step of gastric acid secretion by irreversibly blocking H⁺–K⁺-ATPase in parietal cells. The proton pump works to achieve a million-fold H⁺ gradient by pumping cytoplasmic H₃O⁺ out of the cell into the lumen in exchange for K⁺. The enzyme is stimulated by ligands (histamine/gastrin) to move from an inactive form on tubulovesicles to an active form in the secretory canaliculus. When it becomes activated, the enzyme undergoes conformational changes between the E1 state, in which the H₃O⁺ is bound on the cytoplasmic side, and E2, in which K⁺ is bound on the luminal side. Continuous activity of the proton pump requires recycling of K⁺ back into the lumen through the acid-sensitive KCNQ1/KCNE2 channel, which is open at pH 1. Secretion of HCO₃⁻ is necessary to preserve electroneutrality. PPIs take advantage of this transport system because they are acid-activated prodrugs that convert into sulfenamide derivatives. The reactive sulfenamides link to cysteine residues of the pump's α-subunit by the formation of disulfide bridges. The ion transport and conformational changes are now blocked for the lifetime of the enzyme, and acid secretion is inhibited until new pumps are produced.

Fig. 1 General chemical structure and mechanism of action of proton pump inhibitors (PPIs). (Ward R M, Kearns G L. 2013)

PLGA NPs loaded with esomeprazole (ESO)(ESO-NPs) were developed by Cerioli and colleagues with the goal of altering the intracellular pH in a panel of different melanoma cell lines (501 mel, LM38, LM47, and LM56). ESO-NPs are taken up by melanoma cells and accumulate in melanosomal/lysosomal compartments where they release ESO, resulting in a reduction of acidity and melanin content, possibly by inhibition of tyrosinase activity. Thus, the endolysosomal compartment of cancer cells is disrupted by a pH alteration that may also affect autophagy, with possible consequences for tumor immune escape and cancer progression.

Fig. 2 PLGA nanoparticles loaded with esomeprazole reprogram the tumor microenvironment and alleviate immunosuppression. (Cerioli N, et al. 2025)