Dual functional octreotide-modified liposomal irinotecan leads to high therapeutic efficacy for medullary thyroid carcinoma xenografts
Dual functional octreotide-modified liposomal irinotecan leads to high therapeutic efficacy for medullary thyroid carcinoma xenografts
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DOI：
10.1111/j.1349-7006.2011.02128.x
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发表时间：
2012-02-01
期刊：
影响因子：
5.7
通讯作者：
Maitani, Yoshie
中科院分区：
文献类型：
--
作者：
Iwase, Yuko;Maitani, Yoshie
甲状腺髓样癌是一种罕见的内分泌肿瘤，表现为生长抑素受体亚型2过度表达。甲状腺髓样癌尚无全身治疗方法。此前我们曾报道，与游离伊立替康或非靶向非聚乙二醇化脂质体伊立替康相比，负载伊立替康的奥曲肽-PEG脂质体针对生长抑素受体亚型2，对甲状腺髓样癌异种移植物显示出较高的治疗效果。在本研究中，我们与聚乙二醇化脂质体相比，评估了负载伊立替康的奥曲肽-PEG脂质体的伊立替康及其活性代谢物的生物分布及其治疗效果。此外，为了阐明细胞结合后奥曲肽配体的作用，我们使用未负载药物的空奥曲肽-PEG脂质体评估了肿瘤细胞的细胞毒性以及对肿瘤细胞和异种移植物中蛋白质磷酸化的抑制。在一项治疗研究中，与聚乙二醇化脂质体相比，载有伊立替康的奥曲肽-PEG 脂质体显着提高了中位生存期。注射后6小时的肿瘤组织中，与聚乙二醇化脂质体处理的小鼠相比，奥曲肽-PEG脂质体处理的小鼠显示出明显更高浓度的伊立替康和7-乙基-10-氢化喜树碱，表明奥曲肽-PEG脂质体在肿瘤中快速积累并达到高水平。此外，空奥曲肽-PEG脂质体在体外和体内抑制p70S6K的磷酸化。这些研究结果表明，奥曲肽-PEG脂质体伊立替康具有靶向肿瘤递送和辅助细胞毒性的双重功能，这使得对甲状腺髓样癌异种移植物的治疗效果比聚乙二醇化脂质体更高。 （癌症科学 2012 年；103：310316）
Medullary thyroid carcinoma is a rare endocrine tumor, which shows overexpression of somatostatin receptor subtype 2. There is no systemic therapy for medullary thyroid carcinoma. Previously we reported that octreotide-PEG liposomes loaded with irinotecan, which target somatostatin receptor subtype 2, showed high therapeutic efficacy for medullary thyroid carcinoma xenografts compared with free irinotecan or non-targeted non-PEGylated liposomal irinotecan. In this study, we evaluated octreotide-PEG liposomes loaded with irinotecan in terms of the biodistribution of irinotecan and its active metabolite, and its therapeutic efficacy, compared with PEGylated liposomes. Furthermore, to elucidate the effect of octreotide ligand after cellular association, we assessed the cytotoxicity in tumor cells and the inhibition of protein phosphorylation in the tumor cells and xenografts using empty octreotide-PEG liposomes, which were loaded with no drug. In a therapeutic study, octreotide-PEG liposomes loaded with irinotecan significantly improved median survival compared with PEGylated liposomes. In tumor tissue at 6 h after injection, octreotide-PEG liposome-treated mice showed significantly higher concentrations of irinotecan and 7-ethyl-10-hydrocamptothecin compared with PEGylated liposome-treated mice, indicating that octreotide-PEG liposomes accumulated rapidly and to a high level in the tumor. Furthermore, empty octreotide-PEG liposome inhibited the phosphorylation of p70S6K in vitro and in vivo. These findings indicated that octreotide-PEG liposomal irinotecan has dual functions with targeted tumor delivery and assistance of cellular cytotoxicity, which led to higher therapeutic efficacy than PEGylated liposomes for medullary thyroid carcinoma xenografts. (Cancer Sci 2012; 103: 310316)