A linear polyethylenimine (LPEI) drug conjugate with reversible charge to overcome multidrug resistance in cancer cells

Targeted charge-reversal LPEI conjugate structure and its acid-triggered charge reversal (A) and nuclear drug delivery (B): The negatively charged drug conjugate accumulates in cancer tissues via the enhanced permeation and retention effect; it is taken up by the cancer cells via folate receptor-mediated endocytosis, transferred into an endosome and then a lysosome; the labile amides hydrolyze at the acidic tumor microenvironment (pH < 7.0), endosome (pH = 6.0-6.5) and lysosome (pH = 4.5-5.5) to regenerate the LPEI as the carrier. The regenerated LPEI carrier ruptures the lysosomal membrane to escape into the cytosol and traverse into the nucleus and releases the carried drug there.310