Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker
Camptothecin delivery systems: enhanced efficacy and tumor accumulation of camptothecin following its conjugation to polyethylene glycol via a glycine linker
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DOI：
10.1007/s002800050837
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发表时间：
1998-10-01
影响因子：
3
通讯作者：
Shum, KL
中科院分区：
文献类型：
--
作者：
Conover, CD;Greenwald, RB;Shum, KL
目的：本研究旨在评估聚乙二醇（PEG）偶联喜树碱-20- o -甘氨酸、PEG- β -喜树碱（PEG- β - cpt）的循环潴留、抗肿瘤活性和组织生物分布。peg - β -CPT是天然衍生抗肿瘤药物20-(S)-喜树碱（CPT）的一种新型水溶性转运形式（大分子前药）。方法：对非荷瘤小鼠静脉注射875 mg/kg peg - β - cpt进行循环潴留研究。对裸鼠异种移植瘤模型进行腹腔和静脉注射抗肿瘤活性评价。我们在携带大肠癌异种移植物的裸鼠身上进行了生物分布研究，并给它们注射了氚标记的peg - β -CPT和静脉注射CPT。结果：peg - β -CPT的血t（1/2 α）约为6分钟，血t（1/2 α）约为10.2小时。在所有处理过的异种移植物模型中，我们都看到了显著的抗肿瘤活性。生物分布研究表明，生理盐水中的peg - β -CPT比溶解在脂质内的未共轭CPT在循环中提供更多可用的标记CPT。此外，当以peg - β -CPT形式递送时，似乎有更多的标记CPT在实体肿瘤中积累，并且更倾向于肿瘤组织而不是正常组织。结论：CPT的可溶性转运形式及其基础技术在治疗实体瘤方面具有一定的临床应用价值。
Purpose: This study was designed to assess the circulatory retention, antitumor activity and tissue biodistribution of polyethylene glycol (PEG)-conjugated camptothecin-20-O-glycinate, PEG-beta-camptothecin (PEG-beta-CPT). PEG-beta-CPT is a novel water-soluble transport form (macromolecular prodrug) of the naturally derived antitumor drug, 20-(S)-camptothecin (CPT). Methods: Circulatory retention studies were performed in nontumor-bearing mice injected intravenously (i.v.) with 875 mg/kg of PEG-beta-CPT. Antitumor activity was evaluated both intraperitoneally (i.p.) and i.v. in nude mouse xenograft models. Biodistribution studies were performed in nude mice bearing colorectal carcinoma xenografts with tritium-labelled PEG-beta-CPT and CPT injected i.v. Results: PEG-beta-CPT had a blood t(1/2 alpha) of approximately 6 min and a t(1/2 beta) of 10.2 h. Significant antitumor activity was seen in all treated xenograft models. Biodistribution studies demonstrated that PEG-beta-CPT in saline provided more available labelled CPT in the circulation than unconjugated CPT dissolved in intralipid. In addition, it appeared that more labelled CPT accumulated in solid tumors when delivered in the PEG-beta-CPT form, with greater preference for tumor tissue than normal tissue. Conclusion: This soluble transport form of CPT and its underlying technology may have clinical application especially for the treatment of solid tumors.