Bogdanov A A, Martin C, Bogdanova A V, Brady T J, Weissleder R
Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129.
Bioconjug Chem. 1996 Jan-Feb;7(1):144-9. doi: 10.1021/bc950089b.
A noncovalent adduct of the antineoplastic drug cis-diamminedichloroplatinum (cDDP) and a biocompatible graft copolymer of poly(L-lysine) and methylpoly(ethylene glycol) succinate is described. Upon incubation of cDDP with [O-methylpoly(ethylene glycol)-O'-succinyl]-N- epsilon-poly(L-lysine)n-N-epsilon-succinate, n = 250-270, highly soluble, long circulating adducts were formed which contained 4.3% of platinum by weight. Approximately 60% of the polymer-associated drug was released during dialysis against saline or serum albumin containing saline, with a half-time of release of 63 h. The adducts showed a pronounced antineoplastic effect in BT-20 human adenocarcinoma cell cultures. In cell proliferation assays, the concentration of half-inhibition of [3H]thymidine uptake was 0.9 +/- 0.2 microM for the drug-copolymer adduct compared to 0.3 +/- 0.1 microM for free cDDP. The adduct showed a long blood half-life (ca. 14 h in rats) and accumulated in experimental mammary adenocarcinomas at 2.5-3.5% injected dose per gram of tissue. A control adduct of cDDP with the backbone portion of the copolymer, poly(L-lysine)-N-epsilon-succinate, had a short half-life in the bloodstream (ca. 30 min) and low accumulation (0.5% injected dose per gram) in tumor. A dual therapeutical effect of methylpoly(ethylene glycol)succinylpoly(L-lysine)-succinate as a carrier of cDDP is suggested: (1) as a carrier for systemic release of the active drug from the macromolecule while it circulates in the bloodstream and (2) as a carrier for on-site delivery which results from the release of the drug in the tumor as a consequence of accumulation of the copolymer in the tumor.
本文描述了抗肿瘤药物顺二氨二氯铂（cDDP）与聚（L-赖氨酸）和聚乙二醇琥珀酸甲酯的生物相容性接枝共聚物形成的非共价加合物。将cDDP与[O-甲基聚（乙二醇）-O'-琥珀酰基]-N-ε-聚（L-赖氨酸）n-N-ε-琥珀酸酯（n = 250 - 270）孵育后，形成了高度可溶、循环时间长的加合物，其铂含量为4.3%（重量）。在对含生理盐水或血清白蛋白的生理盐水进行透析时，约60%与聚合物结合的药物被释放，释放半衰期为63小时。该加合物在BT - 20人腺癌细胞培养中显示出显著的抗肿瘤作用。在细胞增殖试验中，药物 - 共聚物加合物对[³H]胸苷摄取的半抑制浓度为0.9±0.2微摩尔，而游离cDDP为0.3±0.1微摩尔。该加合物的血液半衰期较长（大鼠约为14小时），并以每克组织2.5 - 3.5%的注射剂量在实验性乳腺腺癌中蓄积。cDDP与共聚物主链部分聚（L-赖氨酸）-N-ε-琥珀酸酯的对照加合物在血液中的半衰期较短（约30分钟），在肿瘤中的蓄积量较低（每克0.5%注射剂量）。由此表明聚乙二醇琥珀酰聚（L-赖氨酸）-琥珀酸酯作为cDDP载体具有双重治疗作用：（1）作为载体，在其于血液中循环时使活性药物从大分子中全身释放；（2）作为载体，由于共聚物在肿瘤中蓄积导致药物在肿瘤中释放，从而实现局部给药。
