Abstract
We developed pH-controllable cell-penetrating polypeptides (PCCPs) undergoing pH-induced conformational transitions. Unlike natural cell-penetrating peptides, PCCPs was capable of penetrating the plasma membranes dominantly at tumor pH, driven by pH-controlled helicity. The conformation of PCCPs at neutral pH showed low helical propensity because of dominant electrostatic attractions within the side chains. However, the helicity of PCCPs was considerably augmented by the balance of electrostatic interactions, thereby inducing selective cellular penetration. Three polypeptides undergoing different conformational transitions were prepared to verify the selective cellular uptake influenced by their structures. The PCCP undergoing low-to-high helical conformation provided the tumor specificity and enhanced uptake efficiency. pH-induced conformation-transformable polypeptide might provide a novel platform for stimuli-triggered targeting systems.
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