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

Abstract

To improve therapeutic indexes of gemcitabine (GEM), a stimuli-responsive dendritic polyHPMA copolymer conjugated with gemcitabine (Dendritic polyHPMA-GEM) prodrug was designed and synthesized via one-pot synthesis of RAFT polymerization. The prodrug with dendritic architectures is able to aggregate and form stable nanoscale system with a size of 46 nm. The dendritic prodrug with high molecular weight (HMW) of 168 kDa can biodegrade to low molecular weight (LMW, 29 kDa) segments for excretion. The prodrug demonstrates enzyme-responsive drug release features, and over 95% GEM was released from the carrier with the Cathepsin B within 3 h. The cellular mechanism of the dendritic prodrug was studied, suggesting the cytotoxicity is associated with the cell uptake and cell apoptosis. The prodrug shows good hemocompatibility and in vivo biosafety. Of interest, the dendritic polymer prodrug displays high accumulation within tumors, and markedly improves the in vivo antitumor activity against 4T1 murine breast cancer model compared to the free GEM. These in vivo antitumor activities are characterized as with markedly suppressed tumor volumes, indicating as the much higher tumor growth inhibition (TGI 83%) than that in GEM treatment (TGI, 36%), moreover some tumors are eliminated. The tumor xenograft immunohistochemistry study clearly indicates that the tumor apoptosis is through antiangiogenic effects. These results suggest that the stimuli-responsive dendritic polymer-gemcitabine has great potential as an efficient anticancer agent