Journal Article

Trastuzumab- and Fab′ fragment-modified curcumin PEG-PLGA nanoparticles: preparation and evaluation in vitro and in vivo

Wang, Aiping, Ni, Ling, Li, Youxin, Jiang, Ying, Mu, Hongjie, Duan, Dongyu, Sun, Kaoxiang, Yan, Xiuju, Zhang, Liping, Wu, Zimei

2018

Overview

Nanoparticles (NPs) modified with bio-ligands represent a promising strategy for active targeted drug delivery to tumour. However, many targeted ligands, such as trastuzumab (TMAB), have high molecular weight, limiting their application for targeting. In this study, we prepared Fab' (antigen-binding fragments cut from TMAB)-modified NPs (Fab'-NPs) with curcumin (Cur) as a model drug for more effective targeting of human epidermal growth factor receptor 2 (HER2/ErbB2/Neu), which is overexpressed on breast cancer cells. The release kinetics was conducted by dialysis bags. The ability to kill HER2-overexpressing BT-474 cells of Fab'-Cur-NPs compared with TMAB-Cur-NPs was conducted by cytotoxicity experiments. Qualitative and quantitative cell uptake studies using coumarin-6 (fluorescent probe)-loaded NPs were performed by fluorescence microscopy and flow cytometry. Pharmacokinetics and biodistribution experiments in vivo were assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The release kinetics showed that both Fab'-Cur-NPs and TMAB-Cur-NPs provided continuous, slow release of curcumin for 72 h, with no significant difference. In vitro cytotoxicity experiments showed that Fab'-Cur-NPs manifested prominent ability to kill HER2-overexpressing BT-474 cells compared with TMAB-Cur-NPs. Qualitative and quantitative cell uptake studies indicated that the accumulation of Fab'-NPs was greater than that of TMAB-NPs in BT-474 (HER2+) cells; However, there was no significant difference in MDA-MB-231 (HER2-) cells. Pharmacokinetics and biodistribution experiments in vivo demonstrated that the half-life (t1/2) and area under the blood concentration-time curve (AUC0-t) of Fab'-Cur-NPs increased 5.30-fold and 1.76-fold relative to those of TMAB-Cur-NPs, respectively. Furthermore, the tumor accumulation of Fab'-Cur-NPs was higher than that of TMAB-Cur-NPs. Fab' fragment has greater capacity than the intact antibody to achieve tumor targeting through NP-based delivery.

• Publisher: Dove Medical Press Limited,Taylor & Francis Ltd,Dove Press,Dove Medical Press
• Subject: Animals / Antibodies / Antigens / biodistribution / Breast cancer / Cancer / Cancer cells / Cell Death / Cell Line, Tumor / Chemical bonds / Chromatography / Comparative analysis / Coumarins - chemistry / Curcumin / Curcumin - chemical synthesis / Curcumin - pharmacokinetics / Curcumin - therapeutic use / Drug delivery systems / Drugs / Efficiency / Endocytosis / Epidermal growth factors / Fab'-modified curcumin nanoparticles / Fab′-modified nanoparticles / Female / Flow Cytometry / Fluorescence / Fluorescence microscopy / Humans / Immunoglobulin Fab Fragments - chemistry / Immunoglobulins / Immunotherapy / Injections, Intravenous / Laboratory animals / Ligands / Liquid chromatography / Mass spectrometry / Medical imaging / Mice, Inbred BALB C / Microscopy / Microscopy, Fluorescence / Monoclonal antibodies / Nanoparticles / Nanoparticles - chemistry / Nanoparticles - ultrastructure / Original Research / Particle size / pharmacokinetics / Polyesters - chemistry / Polyethylene glycol / Polyethylene Glycols - chemistry / Polyvinyl alcohol / Proteins / Rats, Sprague-Dawley / Spectroscopy / Targeted cancer therapy / Thiazoles - chemistry / Tissue Distribution / Trastuzumab / Trastuzumab - pharmacokinetics / Trastuzumab - therapeutic use / trastuzumab-modified curcumin nanoparticles / Tumors / tumour targeting