Debotton Nir, Parnes Marcela, Kadouche Jean, Benita Simon
Pharmaceutics Department, School of Pharmacy, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel.
J Control Release. 2008 May 8;127(3):219-30. doi: 10.1016/j.jconrel.2008.01.014. Epub 2008 Feb 8.
The aim of this study was to design a new one step conjugation of monoclonal antibodies (MAbs) to surface activated pegylated polyester nanoparticles (NPs) and evaluate the pharmacokinetic profile and therapeutic effect of paclitaxel palmitate (pcpl) loaded anti-HER2 immunoNPs in mice as compared to pcpl solution and NPs following IV injection. The density of the antibody conjugated to the NPs was found to be around 35 MAbs/NP (70% coupling efficiency). In vitro cell culture studies showed good binding and uptake results when immunoNPs were incubated with PC-3 and CAPAN-1 cell lines. Both pcpl NPs and immunoNPs showed significant increased t1/2, C(max) and AUC values as compared to the values of pcpl solution in mice. There was no significant difference in the C(max) and AUC values between pcpl NPs and pcpl immunoNPs. However, the immunoNPs concentrated much less in the liver and spleen than NPs. The pharmacokinetic behavior of the immunoNPs was markedly different from the pharmacokinetic profile of the naked MAb showing that the MAb lost its intrinsic molecular pharmacokinetic properties following conjugation to the NPs. The immunoNPs elicited a significant anti-tumor activity as compared to the pcpl solution and NPs, although the tumor growth was not fully inhibited.
本研究的目的是设计一种将单克隆抗体（MAb）与表面活化的聚乙二醇化聚酯纳米颗粒（NP）进行一步偶联的新方法，并评估静脉注射后，与紫杉醇棕榈酸酯（pcpl）溶液和纳米颗粒相比，负载紫杉醇棕榈酸酯的抗HER2免疫纳米颗粒在小鼠体内的药代动力学特征和治疗效果。发现与纳米颗粒偶联的抗体密度约为35个单克隆抗体/纳米颗粒（偶联效率为70%）。体外细胞培养研究表明，当免疫纳米颗粒与PC-3和CAPAN-1细胞系孵育时，具有良好的结合和摄取结果。与小鼠体内pcpl溶液的值相比，pcpl纳米颗粒和免疫纳米颗粒的t1/2、C(max)和AUC值均显著增加。pcpl纳米颗粒和pcpl免疫纳米颗粒的C(max)和AUC值没有显著差异。然而，免疫纳米颗粒在肝脏和脾脏中的浓度比纳米颗粒低得多。免疫纳米颗粒的药代动力学行为与裸单克隆抗体的药代动力学特征明显不同，表明单克隆抗体与纳米颗粒偶联后失去了其固有的分子药代动力学特性。与pcpl溶液和纳米颗粒相比，免疫纳米颗粒具有显著的抗肿瘤活性，尽管肿瘤生长没有被完全抑制。
