Poly (l-glutamic acid)-g-methoxy poly (ethylene glycol)-gemcitabine conjugate improves the anticancer efficacy of...

Gemcitabine is widely used for anticancer therapy. However, its short blood circulation time and poor stability greatly impair its application. To solve this problem, we prepared a poly (l-glutamic acid)-g-methoxy poly (ethylene glycol)-gemcitabine conjugate (l-Gem) with a 14.3 wt% drug-loading content. l-Gem showed concentration- and time-dependent cytotoxicity towards 4T1, LLC, MIA PaCa-2 and A2780 in vitro. Pharmacokinetic and biodistribution studies indicated that l-Gem had remarkably enhanced blood stability, prolonged blood circulation time and greatly improved selective tumor distribution compared with free gemcitabine. The area under the concentration-time curve from zero to infinity [AUC_(0-∞)] of l-Gem in plasma was 43-fold higher than that of free gemcitabine. The AUC_(0-∞) of the inactive metabolite, 2'-deoxy-2',2'-difluorouridine in the l-Gem group was ∼20% of that observed in the free gemcitabine group. The drug tumor accumulation ratio in the l-Gem group relative to the free gemcitabine group was 9.9 at 36 h, while the tumor AUC ratio was 15.8. Testing on Balb/C mice bearing the 4T1 tumor further demonstrated that l-Gem had significantly higher anticancer efficacy than free gemcitabine in vivo. These findings indicated that l-Gem has great potential for cancer treatment.