Synthesis and evaluation of conjugates of gemcitabine and polyglutamic acid with amino acids as linkers / 国际药学研究杂志

ABSTRACT

Objective: To design and synthesize conjugates of polyglutamic acid and gemcitabine with different amino acids as linkers, and through changing the structure to control the release of free drug and improve antitumor activity. Methods: First, the amino acid esters formed with 3′-OH or 5′-OH of gemcitabine were synthesized, and then the free amino groups of amino acid esters were conjugated with the carboxyl groups in polyglutamic acid to obtain the object conjugate of polyglutamic acid and gemcitabine with different amino acids as linkers. The content of gemcitabine in the conjugates was determined by UV. The release rate of free drug from the conjugates was determined by HPLC. Results and Conclusion: 11 novel conjugates were synthesized with gemcitabine content of 25%-30%. In vitro drug release experiment results revealed that gemcitabine could be released from the conjugates steadily. Conjugates with different amino acids as linkers exhibited different drug release rate. PG-Ala-3′-Gem can release 50% of gemcitabine in 4 h, but PG-Val-3′-Gem and PG-Ala-5′-Gem only can release 30.3% or 43.5% of gemcitabine in 48 h,respectively. The drug release rate in blood is faster than that in water solution.