Plasma membrane lipid bilayer in acidic microenvironment

The plasma membrane lipid bilayer in an acidic microenvironment is a physiological target utilized for the selective delivery of therapeutic and diagnostic agents. In many pathological conditions, most notably solid tumors, the extracellular environment becomes acidic (pH 6.0–6.8) due to the Warburg effect, where cancer cells favor glycolysis over oxidative phosphorylation, leading to lactic acid accumulation (Gatenby & Gillies, 2004 [1]). This localized acidity distinguishes the diseased tissue from healthy tissue, which maintains a physiological pH of approximately 7.4. Drugs designed for this target, such as pH-Low Insertion Peptides (pHLIPs), exploit this pH gradient; at neutral pH, these peptides are unstructured and reside on the membrane surface, but upon protonation in an acidic environment, they form an alpha-helix that inserts across the lipid bilayer (Reshetnyak et al., 2006 [2]). This mechanism allows for the direct translocation of membrane-impermeable molecules, such as toxins or imaging dyes, into the cytoplasm or their tethering to the cell surface (Andreev et al., 2014 [3]). Beyond oncology, this target is relevant in treating inflammation and ischemia, where metabolic stress similarly lowers local pH (Liu et al., 2013 [4]). By targeting the physical state of the membrane in these specific environments, researchers can achieve high therapeutic indices and reduced systemic toxicity.

Other names

Acidic tumor microenvironment lipid bilayerpH-sensitive membraneAcidic cell surfaceTME lipid bilayer

pH-dependent transmembrane insertion and cargo delivery