Cell membrane lipid bilayer in acidic extracellular microenvironments

The cell membrane lipid bilayer in acidic extracellular microenvironments is a specialized physiological target defined by a localized decrease in pH, typically between 6.0 and 6.8. This phenomenon is predominantly observed in the tumor microenvironment (TME) due to the Warburg effect, where accelerated glycolysis and poor vascularization lead to the accumulation of lactic acid and protons (Gatenby & Gillies, 2004, Nature Reviews Cancer). Similar acidic conditions occur in ischemic tissues, sites of chronic inflammation, and areas of infection. This target is utilized for site-specific drug delivery by exploiting the pH-dependent protonation of therapeutic carriers or peptides. For instance, pH-Low Insertion Peptides (pHLIPs) undergo a conformational change from an unstructured state to an alpha-helical structure that inserts into the lipid bilayer specifically under acidic conditions (Reshetnyak et al., 2006, PNAS). This mechanism enables the selective delivery of imaging agents or toxins to diseased cells while sparing healthy tissues at physiological pH (7.4). Consequently, the acidic lipid bilayer acts as a molecular switch for the targeted release or membrane-translocation of various therapeutic payloads (Andreev et al., 2014, Frontiers in Physiology).

Other names

Acidic tumor microenvironment cell membraneLow-pH cell membraneAcidic lipid bilayerTumor extracellular matrix-membrane interface

The primary mechanism involves the pH-dependent protonation of acidic residues (e.g., Asp, Glu) or lipid headgroups, which increases hydrophobicity and triggers the insertion of peptides or the destabilization of pH-sensitive carriers to release cargo directly at the cell membrane or into the cytoplasm.