Yang Tao, Choi Min-Koo, Cui Fu-De, Lee Seung-Jin, Chung Suk-Jae, Shim Chang-Koo, Kim Dae-Duk
College of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, People's Republic of China.
Pharm Res. 2007 Dec;24(12):2402-11. doi: 10.1007/s11095-007-9425-y. Epub 2007 Sep 9.
The antitumor effect of paclitaxel-loaded PEGylated immunoliposome (PILs) was investigated in breast cancer cell lines and the xenograft model.
Herceptin was conjugated to paclitaxel-loaded PEGylated liposomes (PLs). In vitro cellular uptake and cytotoxicity of PILs were determined in breast cancer cell lines while in vivo antitumor efficacy was evaluated in the xenograft nude mouse model.
The PILs formulation was able to significantly increase the HER2 mediated cellular uptake of paclitaxel compared to the PLs in cell lines overexpressing HER2 (BT-474 and SK-BR-3 cells). However, in the MDA-MB-231 cells, which express low levels of HER2, the difference between the PILs and PLs formulation was not significant. The biological activity of Herceptin was maintained throughout the conjugation process as exhibited by the antitumor dose-response curves determined for Herceptin itself, for the thiolated Herceptin alone and subsequently for the immunoliposome-coupled Herceptin. In BT-474 and SK-BR-3 cells, the cytotoxicity of the PILs was more potent than that of Taxol. Moreover, in in vivo studies, PILs showed significantly higher tumor tissue distribution of paclitaxel in the BT-474 xenograft model and more superior antitumor efficacy compared to Taxol and PLs. However, in the MDA-MB-231 xenograft model, PILs and PLs showed similar tumor tissue distribution as well as antitumor activity.
These results suggest that HER2-mediated endocytosis is involved in the PILs formulation. The ability of the PILs formulation to efficiently and specifically deliver paclitaxel to the HER2-overexpressing cancer cells implies that it is a promising strategy for tumor-specific therapy for HER2-overexpressing breast cancers.
研究载紫杉醇聚乙二醇化免疫脂质体（PILs）在乳腺癌细胞系和异种移植模型中的抗肿瘤作用。
将赫赛汀与载紫杉醇聚乙二醇化脂质体（PLs）偶联。在乳腺癌细胞系中测定PILs的体外细胞摄取和细胞毒性，同时在异种移植裸鼠模型中评估其体内抗肿瘤疗效。
在过表达HER2的细胞系（BT-474和SK-BR-3细胞）中，与PLs相比，PILs制剂能够显著增加HER2介导的紫杉醇细胞摄取。然而，在HER2表达水平较低的MDA-MB-231细胞中，PILs和PLs制剂之间的差异不显著。在整个偶联过程中，赫赛汀的生物学活性得以保持，这通过对赫赛汀本身、单独的硫醇化赫赛汀以及随后的免疫脂质体偶联赫赛汀测定的抗肿瘤剂量反应曲线得以体现。在BT-474和SK-BR-3细胞中，PILs的细胞毒性比紫杉醇更强。此外，在体内研究中，与紫杉醇和PLs相比，PILs在BT-474异种移植模型中显示出更高的紫杉醇肿瘤组织分布以及更优的抗肿瘤疗效。然而，在MDA-MB-231异种移植模型中，PILs和PLs显示出相似的肿瘤组织分布以及抗肿瘤活性。
这些结果表明HER2介导的内吞作用参与了PILs制剂。PILs制剂能够有效且特异性地将紫杉醇递送至过表达HER2的癌细胞，这意味着它是一种针对过表达HER2乳腺癌进行肿瘤特异性治疗的有前景的策略。
