Carboxymethyl Chitosan-Modified Polyamidoamine Dendrimer Enables Progressive Drug Targeting of Tumors via pH-Sensitive Charge Inversion.

Polyamidoamine dendrimers are potential candidates for drug delivery systems due to their remarkable cell-penetrating power that results from their strong positive surface charge. However, the positively charged surfaces always lead to serious cytotoxicity and the rapid clearance of polyamidoamine in vivo, which limit the application of these dendrimers. To overcome these drawbacks, we developed a carboxymethyl chitosan-modified polyamidoamine dendrimer to achieve progressive drug targeting of tumors via pH-sensitive charge inversion. With the shielding of carboxymethyl chitosan, the complex was negatively charged at physiological conditions (pH 7.4) and prone to enrich at tumor sites due to the enhanced permeation and retention effect; however, it regained a positive charge via the removal of the carboxymethyl chitosan coating under tumor-acidic conditions (pH 6.5) and achieved high intracellular uptake in tumor cells through electrostatic adsorptive endocytosis. In this study, these dendrimers exhibited 1.99- and 1.76-times higher cellular uptake efficiencies at pH 7.4 in MCF-7 or A549 cells, respectively, compared with efficiencies at pH 6.5, indicating an effective pH-dependent accumulation; the fluorescence intensities of these cells exposed to the dendrimers at pH 6.5 were also 16.45- and 9.27-fold greater, respectively, than those of free doxorubicin. After intravenous administration in mice bearing H22 tumors, doxorubicin-loaded dendrimers exhibited a 1.50-fold greater antitumor activity and presented no obvious systematic toxicity based on histological analysis compared with free drugs. Overall, a simple decoration of carboxymethyl chitosan demonstrated to be a promising way for cationic nanocarriers to achieve pH-sensitive drug release and charge conversion response to tumor microenvironment pH and enhance the antitumor therapy efficiency of anticancer drugs.