Lipid bilayer of cell membranes in acidic tumor microenvironments

The lipid bilayer of cell membranes within the acidic tumor microenvironment (TME) serves as a unique physical target for selective drug delivery and imaging. Due to the Warburg effect, cancer cells exhibit increased glycolysis and lactic acid secretion, resulting in an extracellular pH (pHe) significantly lower (pH 6.2–6.8) than that of healthy tissues (pH 7.4) [1]. This acidity triggers conformational changes in specialized molecules, such as pH-Low Insertion Peptides (pHLIPs), which transition from an unstructured state to an alpha-helical form that inserts directly into the lipid bilayer [2]. This mechanism allows for the targeted delivery of imaging isotopes or cytotoxic payloads specifically to the tumor site while sparing healthy cells [3]. Beyond pHLIPs, pH-sensitive liposomes and polymers utilize this environmental cue to destabilize and release their contents upon contact with the acidic membrane [4]. Consequently, the TME lipid bilayer is a critical interface for overcoming the lack of specific surface receptors in many aggressive cancers [5]. However, therapeutic challenges include potential off-target effects in other acidic physiological sites, such as the kidneys or areas of inflammation and ischemia [6]. Citations: [1] Webb, B. A., et al. (2011). "Dysregulated pH: a perfect storm for cancer progression." Nature Reviews Cancer. [2] Reshetnyak, Y. K., et al. (2006). "Measuring condition-dependent membrane-peptide interactions." PNAS. [3] Wyatt, L. C., et al. (2017). "Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors." Trends in Biotechnology. [4] Liu, J., et al. (2013). "pH-sensitive nano-systems for cancer therapy." Nanoscale. [5] Anderson, M., et al. (2013). "The role of glycolysis and acidosis in tumor progression." Cancer and Metastasis Reviews. [6] Andreev, O. A., et al. (2014). "Mechanism and uses of a membrane peptide that targets tumors and other acidic tissues." Frontiers in Physiology.

Other names

Acidic tumor cell membraneTumor cell lipid bilayerAcidic TME lipid bilayerpH-sensitive lipid bilayer

pH-dependent membrane insertion and translocation of cargo; pH-triggered destabilization of lipid bilayers for drug release.