Cathepsin B-Sensitive and Biocompatible Dendritic polyHPMA-Gemcitabine Prodrug-Based Nanoscale System Markedly Enhances the Antitumor Activity

In an attempt to improve the therapeutic indices of gemcitabine (GEM), a prodrug was designed by conjugating GEM with a stimuli-responsive dendritic polyHPMA copolymer (dendritic polyHPMA-GEM) and synthesized using the one-pot method of RAFT polymerization. The prodrug with dendritic architectures was able to aggregate and form stable nanoscale systems in the order of 46 nm. The high molecular weight (HMW, 168 kDa) dendritic prodrug could biodegrade into segments of low molecular weight (LMW, 29 kDa) for excretion. The prodrug demonstrates enzyme-responsive drug release features; over 95% GEM was released from the carrier in the presence of cathepsin B within 3 h. Investigation of the cellular mechanism underlying the dendritic prodrug suggests that cytotoxicity is associated with cellular uptake and cell apoptosis. The prodrug shows good hemocompatibility and in vivo biosafety. In particular, the dendritic polymer prodrug displays high accumulation within tumors and markedly improved in vivo antitumor activity in the 4T1 murine breast cancer model compared to free GEM. The in vivo antitumor activities are characterized by a marked suppression in tumor volumes indicating much higher tumor growth inhibition (TGI, 83%) than that in GEM treatment (TGI, 36%). In addition, some tumors were eliminated. The tumor xenograft immunohistochemistry study clearly indicates that tumor apoptosis occurs through antiangiogenic effects. These results suggest that the stimuli-responsive dendritic polymer-gemcitabine has great potential as an efficient anticancer agent.