Cellular phospholipid bilayer in acidic tumor microenvironment

The cellular phospholipid bilayer in the acidic tumor microenvironment (TME) represents a unique physiological target for the selective delivery of therapeutic and diagnostic agents. This targeting strategy leverages the Warburg effect, a metabolic hallmark of cancer where cells favor glycolysis over oxidative phosphorylation, leading to the secretion of lactic acid and a reduction in extracellular pH to approximately 6.0–6.8 [Cancer Res. 2016;76(13):3637-44]. The primary mechanism for interacting with this target involves pH-Low Insertion Peptides (pHLIPs), which are water-soluble at neutral pH but undergo a conformational transition to form an alpha-helix that inserts into the lipid bilayer under acidic conditions [Biophys J. 2006;91(11):L94-6]. This insertion allows for the precise delivery of various cargoes, including imaging fluorophores, potent toxins, and polar molecules that cannot otherwise cross the cell membrane [Trends Biotechnol. 2017;35(7):653-664]. Unlike protein-based targets, the phospholipid bilayer in an acidic context is a relatively universal feature of solid tumors, potentially bypassing the limitations of tumor heterogeneity and receptor down-regulation. Current clinical development, such as the pHLIP-exatecan conjugate CBX-12, demonstrates the potential of this target to improve the therapeutic index of cytotoxic drugs [Cybrexa Therapeutics]. However, the presence of other acidic environments in the body, such as the kidneys or sites of inflammation, necessitates careful design to minimize off-target toxicity.

Other names

Tumor cell membraneAcidic tumor cell surfaceLow-pH cell membraneTME-associated phospholipid bilayer

pH-dependent membrane insertion or destabilization triggered by the acidic extracellular environment of tumors, typically mediated by pH-Low Insertion Peptides (pHLIPs) that form alpha-helices and insert into the bilayer at low pH [Biophys J. 2006;91(11):L94-6].