Role of cellular uptake in the reversal of multidrug resistance by PEG- b -PLA polymeric micelles

• Published in: Biomaterials 2011-08, Vol.32 (22), p.5148-5157
• Main Authors: Xiao, Ling, Xiong, Xiaoqin, Sun, Xiaohui, Zhu, Yanhong, Yang, Hao, Chen, Huabing, Gan, Lu, Xu, Huibi, Yang, Xiangliang
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - physiology; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Cell Line, Tumor - drug effects; Cell Membrane - metabolism; Cell Membrane - ultrastructure; Cellular uptake; Dentistry; Drug Carriers - chemistry; Drug Carriers - pharmacology; Drug Resistance, Multiple - physiology; Endocytosis - physiology; Fluorescence Resonance Energy Transfer; Humans; Lactates - chemistry; Lactates - metabolism; Materials Testing; Micelles; Microscopy, Atomic Force; Multidrug resistance; Paclitaxel; Paclitaxel - chemistry; Paclitaxel - pharmacology; Particle Size; Pgp; Polyethylene Glycols - chemistry; Polyethylene Glycols - metabolism; Polymeric micelles; Polymers - chemistry; Polymers - metabolism
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2011.03.071

Abstract Understanding the processes involved in the cellular uptake of nanoparticles is critical for developing effective nano drug delivery systems. In this paper we found that PEG- b -PLA polymeric micelles firstly interacted with cell membrane using atomic force microscopy (AFM) and then released their core-loaded agents into the cell membrane by fluorescence resonance energy transfer (FRET). The released agents were internalized into the cells via lipid raft/caveolae-mediated endocytosis using total internal reflection fluorescence microscopy (TIRFM) and endocytic inhibitors. Further studies revealed that paclitaxel (PTX)-loaded PEG- b -PLA micelles (M-PTX) increased the cellular accumulation of PTX in PTX-resistant human ovarian cell line A2780/T which resulted in more apoptosis as measured by flow cytometry and the cleavage of poly (ADP-ribose) polymerase (PARP) compared with free PTX. PEG- b -PLA micelles inhibited P-glycoprotein (Pgp) function and Pgp ATPase activity but had no effect on Pgp protein expression. The membrane microenvironment studies showed that PEG- b -PLA micelles induced cell membrane depolarization and enhanced membrane microviscosity. These results suggested that PEG- b -PLA micelles might inhibit Pgp function to reverse multidrug resistance (MDR) via interaction with cell membrane to affect the membrane microenvironment. This study provides a foundation for understanding the mechanism of reversing MDR by nanoparticles better and designing more effective nano drug carriers.