Conjugation of cell penetrating peptides with pH-sensitive peptides improves drug delivery in acidic environments. A) Scheme showing micelle structure and drug delivery mechanisms of PEG-PLA conjugated with a cell penetrating peptide composed of arginine and glycine (RGO) or charged peptides containing histidine and glutamic acid (HEO). PEG-PLA alone formed micelles that encapsulated the drug and delivered it passively to cells through diffusion (DTX-PM). RGO and HEO formed micelles with the drug encapsulated and the surface of the micelle decorated with peptides (DTX-PHPO). Upon lowering the pH, the micelles were endocytosed by the cells. B) Altering pH sensitivity of micelles by adjusting the ratio of charged peptides to uncharged peptides. RGO alone had a pH-insensitive zeta potential, whereas HEO was pH-sensitive. By increasing the ratio between HEO and RGO in PHPO, the point of zero charge shifted. A ratio of 45:55 HEO:RGO was selected for further testing since the point of zero charge was between the pH values of physiological tumor microenvironmental conditions. Reprinted from International Journal of Pharmaceutics, 466, Ammar Ouahab, Nihad Cheraga, Vitus Onoja, Yan Shen, Jiasheng Tu, Novel pH-sensitive charge-reversal cell penetrating peptide conjugated PEG-PLA micelles for docetaxel delivery: In vitro study. 233–245, Copyright 2014, with permission from Elsevier.