For effective anticancer drug delivery, neutral stealthy nanocarriers are essential to turn into positively charged once accumulated in the tumor site for facilitated tumor penetration, cellular uptake and even nuclear localization. Such a neutral/negative-to-positive charge-reversal is typically realized by acid-catalyzed hydrolysis of b-carboxylic acid amides into amines triggered by the acidity of the tumor microenvironment or the intracellular compartments. However, the clinical relevance of this acid-triggered charge-reversal is limited by the low occurrence of the acidic tumor regions in small human tumors and the inaccessibility of nanocarriers to these weakly acidic regions that are far away from tumor blood vessel network. To this end, we here demonstrate an enzyme-triggered charge-reversal strategy, taking advantage of the more general enzyme overexpression in tumors. γ-Glutamyl transpeptidase (GGT) is highly expressed on the surface of metabolically active tumor cells in aggressive edges and blood vessel periphery of tumors. A γ-glutamylamide-based zwitterionic polymer is long circulating in blood compartment. In GGT-positive tumors, the overexpressed GGT cleaves off the γ-glutamyl moieties to expose primary amine groups, making the polymer positively charged and highly efficient in tumor accumulation, penetration and cell uptake. As a result, its conjugate with camptothecin shows much more potent antitumor activity than non GGT-sensitive ones, leading to complete eradication of small solid tumors (~100 mm3) and dramatic regression of large established tumors with the clinically relevant size (~500 mm3). Furthermore, this conjugate also significantly extends the survival of mice bearing orthotopic pancreatic tumors compared to the first-line drug gemcitabine. Thus, this work demonstrates the first example of enzymatic charge-reversal for design of highly effect cancer nanomedicine.

Enzyme-responsive charge-reversal polymer for enhanced anticancer drug delivery

256th National Meeting (2018)

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