Institute of Medicinal Chemistry, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
Mol Pharm. 2011 Apr 4;8(2):330-7. doi: 10.1021/mp100380y. Epub 2011 Jan 18.
Medullary thyroid carcinoma (MTC) is a rare endocrine tumor that frequently metastasizes, but treatment with irinotecan (CPT-11) is limited because of side effects. MTC is known to overexpress the somatostatin receptor subtype 2 (SSTR2). Octreotide (Oct) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor-targeting ligand. We prepared Oct-targeted liposomes loaded with CPT-11 using Oct-poly (ethylene glycol) (PEG)-lipid and evaluated Oct-mediated association and cytotoxicity of the liposomes with an MTC cell line TT. The association of higher concentrations of modified Oct-targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct-targeted liposomes but not by free Oct. With exposure for 96 h, the cytotoxicity of Oct-targeted liposomal CPT-11 (IC50: 1.05 ± 0.47 μM) was higher than free CPT-11 (IC50: 3.76 ± 0.61 μM) or PEGylated liposomal CPT-11 (IC50: 3.05 ± 0.28 μM). In addition, empty Oct-targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity, suggesting that Oct as a ligand showed cytotoxicity. Moreover, Oct-targeted liposomal CPT-11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT-11 at a one-third dose and lower administration times with free CPT-11. These findings indicated that Oct-targeted liposomes loaded with CPT-11 may offer considerable potential for MTC chemotherapy because cytotoxicity of both CPT-11 and Oct was enhanced by effective cellular uptake via SSTR2.
甲状腺髓样癌（MTC）是一种罕见的内分泌肿瘤，常发生转移，但因其副作用，伊立替康（CPT-11）的治疗受到限制。已知 MTC 过度表达生长抑素受体亚型 2（SSTR2）。奥曲肽（Oct）是一种生长抑素类似物，对 SSTR 具有高亲和力，可用作肿瘤靶向配体。我们使用 Oct-聚乙二醇（PEG）-脂质制备了载有 CPT-11 的 Oct 靶向脂质体，并评估了 MTC 细胞系 TT 中 Oct 介导的脂质体结合和细胞毒性。与 PEG 化脂质体相比，较高浓度的修饰的 Oct 靶向脂质体与 TT 细胞的结合明显更高，并且可以被空的 Oct 靶向脂质体而不是游离的 Oct 显著抑制。暴露 96 小时后，Oct 靶向脂质体 CPT-11（IC50：1.05±0.47 μM）的细胞毒性高于游离 CPT-11（IC50：3.76±0.61 μM）或 PEG 化脂质体 CPT-11（IC50：3.05±0.28 μM）。此外，在游离 Oct 没有显示细胞毒性的浓度下，空的 Oct 靶向脂质体显示出比空的非靶向脂质体更高的细胞毒性，这表明 Oct 作为配体表现出细胞毒性。此外，与非靶向脂质体和游离 CPT-11 相比，载有 CPT-11 的 Oct 靶向脂质体在三分之一剂量和较低的游离 CPT-11 给药次数下，导致明显更高的抗肿瘤活性和延长的生存时间。这些发现表明，载有 CPT-11 的 Oct 靶向脂质体可能为 MTC 化疗提供巨大的潜力，因为 CPT-11 和 Oct 的细胞摄取通过 SSTR2 增强了细胞毒性。
