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Abstract
<p class="first" id="P3">The pH-Low Insertion Peptide (pHLIP) has emerged as an important
tool for targeting
cancer cells; it has been assumed that its targeting mechanism depends solely on the
mild acidic environment surrounding tumors. Here, we examine the role of Ca
<sup>2+</sup> and Mg
<sup>2+</sup> on pHLIP’s insertion, cellular targeting and drug delivery. We demonstrate
that physiologically-relevant
concentrations of either cation can shift the protonation-dependent transition by
up to several pH units towards basic pH and induce substantial protonation-independent
transmembrane insertion of pHLIP at pH as high as 10. Consistent with these results,
the ability of pHLIP to deliver the cytotoxic compound monomethyl-auristatin-F to
HeLa cells is increased several-fold in presence of Ca
<sup>2+</sup>. Complementary measurements with model membranes confirmed this Ca
<sup>2+</sup>/Mg
<sup>2+</sup>-dependent membrane-insertion mechanism. The magnitude of this alternative
Ca
<sup>2+</sup>/Mg
<sup>2+</sup>-dependent effect is also modulated by lipid composition—specifically
by the presence
of phosphatidylserine—providing new clues to pHLIP’s unique tumor targeting ability
in vivo. These results exemplify the complex coupling between protonation of anionic
residues and lipid-selective targeting by divalent cations, which is relevant to the
general signaling on membrane interfaces.
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