Noncanonical amino acids to improve the pH response of pHLIP insertion at tumor acidity.

ABSTRACT: The pH low insertion peptide (pHLIP) offers the potential to deliver drugs selectively to the cytoplasm of cancer cells based on tumor acidosis. The WT pHLIP inserts into membranes with a pH50 of 6.1, while most solid tumors have extracellular pH (pH(e)) of 6.5-7.0. To close this gap, a SAR study was carried out to search for pHLIP variants with improved pH response. Replacing Asp25 with ?-aminoadipic acid (Aad) adjusts the pH50 to 6.74, matching average tumor acidity, and replacing Asp14 with ?-carboxyglutamic acid (Gla) increases the sharpness of pH response (transition over 0.5 instead of 1?pH unit). These effects are additive: the Asp14Gla/Asp25Aad double variant shows a pH50 of 6.79, with sharper transition than Asp25Aad. Furthermore, the advantage of the double variant over WT pHLIP in terms of cargo delivery was demonstrated in turn-on fluorescence assays and anti-proliferation studies (using paclitaxel as cargo) in A549 lung cancer cells at pH?6.6.

SUBMITTER: Onyango JO 

PROVIDER: S-EPMC4427346 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature