Multifunctional pH-sensitive micelles for tumor-specific uptake and cellular delivery

The distinct ability of cell-penetrating peptides (CPPs) has led to the development of novel drug delivery methods in human cells for therapeutic purposes. The lack of specific selectivity is a main obstacle to the widespread use of CPPs. A novel delivery method based on acid-sensitive micelles used for the introduction and protection of TAT was developed. Doxorubicin-TAT conjugate (Dox-TAT) was loaded in the luteinizing hormone-releasing hormone modified poly (ethylene glycol)-poly (L-histidine)-doxorubicin (LHRH-PEG-PHIS-Dox) micelle. Dox was chemically conjugated to the polymer backbone not only to improve the stability of micelles, but also to increase the drug loading efficiency of the micelle. These micelles could dissociate the responding tumor extracellular pH(e) and release Dox-TAT to pass directly through the cell membrane to the cytosol of the multidrug resistant cancer cells. The undissociated micelles could also be actively internalized into the cells by receptor-mediated endocytosis, resulting in high cytotoxicity. LHRH-PEG-PHIS-Dox/ Dox-TAT showed the highest antitumor effects among the four treatment groups in vitro and vivo and showed no remarkable effect on the body weight compared to the control. This skillfully designed system combined the double functions of targeted delivery and TAT-mediated efficient entry, which could increase the antitumor activity, even in drug resistant tumor cells.