Cell plasma membrane phospholipid bilayer in acidic microenvironments

The cell plasma membrane phospholipid bilayer in acidic microenvironments serves as a specialized therapeutic target, particularly in the context of the tumor microenvironment (TME). Due to the Warburg effect and poor perfusion, many solid tumors exhibit an extracellular pH (pHe) significantly lower (pH 6.0–6.8) than that of healthy tissue (pH 7.4) [1]. This acidity can be exploited to trigger the insertion of pH-Low Insertion Peptides (pHLIPs) or the release of cargo from pH-sensitive nanocarriers directly into or across the cell membrane [2]. In these acidic conditions, protonation of specific residues (such as aspartate or glutamate) reduces the hydrophilicity of the targeting moiety, facilitating its partition into the hydrophobic core of the lipid bilayer [3]. This mechanism allows for the selective delivery of imaging agents or cytotoxic drugs to diseased cells while sparing healthy tissues [4]. Beyond oncology, this target is relevant in inflammatory and ischemic conditions where local acidosis occurs [5]. The target is not a single protein but a physical-chemical state of the membrane surface that enables conditional molecular interactions. Therapeutic strategies often involve peptides that form transmembrane helices only when the environmental pH drops below a specific threshold.

Other names

Acidic tumor microenvironment membranepH-sensitive lipid bilayerAcidic cell surfaceLow-pH membrane

The primary mechanism involves the pH-triggered conformational change of targeting moieties, such as pHLIP, which transitions from an unstructured state to a transmembrane alpha-helix upon protonation of acidic residues in low-pH environments [2, 3]. This transition facilitates the direct translocation of membrane-impermeable cargo into the cytoplasm or the stable anchoring of imaging agents to the cell surface [4].