Plasma membrane lipid bilayer in acidic extracellular tumor microenvironment

The plasma membrane lipid bilayer in the acidic extracellular tumor microenvironment (TME) is a distinct physiological target characterized by a lower pH compared to normal tissues. This acidity arises from the Warburg effect, where cancer cells prioritize glycolysis over oxidative phosphorylation, leading to the accumulation of lactic acid and protons in the extracellular space (Gatenby & Gillies, 2004, Nature Reviews Cancer). While the lipid bilayer itself is a universal cellular structure, the specific chemical environment of the TME allows for the selective targeting of tumor cells based on acidity rather than surface protein expression (Webb et al., 2011, Nature Reviews Cancer). Therapeutic strategies often utilize pH-Low Insertion Peptides (pHLIPs), which are water-soluble at neutral pH but form a transmembrane helix that inserts into the bilayer when the pH drops below 7.0 (Reshetnyak et al., 2006, PNAS). This insertion mechanism enables the delivery of various payloads, including fluorescent dyes for surgical imaging, toxins for chemotherapy, and polar molecules that cannot otherwise cross the membrane (Wyatt et al., 2017, Trends in Biotechnology). Additionally, pH-sensitive liposomes and nanoparticles are designed to destabilize or release their contents upon encountering the acidic environment of the tumor membrane (Liu et al., 2013, Advanced Drug Delivery Reviews). This approach is particularly valuable for targeting the heterogeneous cell populations within solid tumors that may lack consistent biomarker expression (Weerakkody et al., 2013, PNAS).

Other names

Tumor cell membraneAcidic tumor microenvironmentLow-pH tumor membraneCancer cell lipid bilayer

pH-triggered transmembrane helix formation and insertion for selective cargo delivery