A pH-sensitive charge-conversion system for doxorubicin delivery.

A novel pH-sensitive charge-conversion shielding system was designed by the electrostatic binding of polyethylenimine (PEI)-poly(l-lysine)-poly(l-glutamic acid) (PELG), PEI, and cis-aconityl-doxorubicin (CAD). Doxorubicin (DOX) was modified by cis-aconityl linkage to form acid-sensitive CAD, which was then adsorbed by the positively charged PEI. The PEI/CAD complexes were subsequently shielded with the pH-responsive charge-conversion PELG. In normal tissues, the PELG/PEI/CAD complexes were negatively charged; in acidic tumor tissues, the shielding PELG was positively charged and detached from the PELG/PEI/CAD complexes. The resulting positively charged PEI/CAD complexes thus became exposed and were endocytosed. CAD was then cleaved in the acidic intracellular environment of endosomes and lysosomes, and converted back into DOX. The charge reversal of the PELG/PEI/CAD complexes was verified by zeta potential analysis at different pH values. Moreover, DOX release increased with decreasing pH. Cell uptake and confocal laser scanning microscopy analyses showed that, at pH 6.8, PELG/PEI/CAD had the highest endocytosis rate and more DOX entered cell nuclei. More importantly, the system showed remarkable cytotoxicity against cancer cells. These results revealed that the combination of pH-sensitive charge-conversion shielding with pH-sensitive drug release is a potential drug delivery system for tumor treatment.