CIS-ACONITYL SPACER BETWEEN DAUNOMYCIN AND MACROMOLECULAR CARRIERS - A MODEL OF PH-SENSITIVE LINKAGE RELEASING DRUG FROM A LYSOSOMOTROPIC CONJUGATE
CIS-ACONITYL SPACER BETWEEN DAUNOMYCIN AND MACROMOLECULAR CARRIERS - A MODEL OF PH-SENSITIVE LINKAGE RELEASING DRUG FROM A LYSOSOMOTROPIC CONJUGATE
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DOI：
10.1016/0006-291x(81)91644-2
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发表时间：
1981-01-01
影响因子：
3.1
通讯作者：
RYSER, HJP
中科院分区：
文献类型：
--
作者：
SHEN, WC;RYSER, HJP
将由相应酸酐制备的柔红霉素[一种抗感染剂]的N-顺式-马来酰基和N-马来酰基衍生物与Affi-Gel 701（氨乙基聚丙烯酰胺珠）和聚（D-赖氨酸）偶联。药物与Affi-Gel 701之间的顺乌头基连接具有pH敏感性，在pH 6或更高时水解半衰期为96 h。< 3 h at pH 4 and >TLC和细胞毒性试验表明，水解产物是未改变的道诺霉素。这些Affi-Gel偶联物在中性pH的WEHI-5 [小鼠白血病]细胞培养基中存在3天，几乎没有或没有生长抑制作用。N-顺乌头基道诺霉素-聚赖氨酸偶联物在相似条件下加入WEHI-5细胞中，对细胞生长的抑制率达90%。相当的N-马来酰基道诺霉素-聚（D-赖氨酸）缀合物的添加不是抑制性的。与Affi-Gel缀合物不同，N-顺式乌头基道诺霉素-聚（D-赖氨酸）进入细胞并到达溶酶体隔室，并且由于游离顺式羧基的参与，顺式乌头基间隔基在溶酶体的酸性环境中从聚（D-赖氨酸）释放道诺霉素。这种释放机制也适用于其他药物-大分子偶联物。
N-cis-Aconityl and N-maleyl derivatives of daunomycin [an antineoplastic antiinfective agent] prepared from the respective anhydrides were conjugated to Affi-Gel 701 (aminoethyl polyacrylamide beads) and to poly(D-lysine). The cis-aconityl linkage between the drug and Affi-Gel 701 is pH-sensitive with a hydrolysis half-life of < 3 h at pH 4 and > 96 h at pH 6 or higher. TLC and cytotoxic tests in cultured cells indicate that the product of hydrolysis is unaltered daunomycin. These Affi-Gel conjugates present for 3 days in the culture medium of WEHI-5 [mouse leukemia] cells at neutral pH have little or no growth inhibitory effect. N-cis-aconityl daunomycin-poly(D-lysine) conjugates added to WEHI-5 cells under comparable conditons cause a 90% inhibition of cell growth. Comparable addition of N-maleyl daunomycin-poly(D-lysine) conjugates is not inhibitory. Unlike the Affi-Gel conjugate, N-cis-aconityl daunomycin-poly(D-lysine) enters cells and reaches the lysosomal compartment, and the cis-aconityl spacer releases daunomycin from poly(D-lysine) in the acidic milieu of lysosomes due to the participation of a free cis-carboxylic group. This releasing mechanism should be applicable to other drug-macromolecular conjugates.