以氨基酸为连接子的吉西他滨-聚谷氨酸偶合物设计、合成及评价

目的 设计、合成抗肿瘤药物吉西他滨与聚谷氨酸的偶合物，通过调节连接子的结构以控制药物的释放，提高抗肿瘤药物的疗效。方法 首先合成吉西他滨3′-或5′-的氨基酸酯衍生物，然后在DCC作用下，氨基酸的氨基与聚谷氨酸分子中的羧基缩合，得到以氨基酸为连接子的吉西他滨-聚谷氨酸偶合物；用紫外法测定偶合物载药量；用HPLC法测定偶合物在水溶液或血浆中的稳定性。结果与结论 共合成目标化合物11个，载药量为25%～30%。稳定性试验结果表明，偶合物在水溶性或血浆中能够稳定地释放游离药物，氨基酸类型及连接位置可影响药物的释放速率，偶合物PG-Ala-3′-Gem的释放速率最快，4 h释放50%的药物，而PG-Val-3′-Gem和PG-Ala-5′-Gem在48 h分别释放30.3%和43.5%；偶合物在血浆中的释放速率略快于水溶液中的释放速率。

Synthesis and evaluation of conjugates of gemcitabine and polyglutamic acid with amino acids as linkers

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.