title: Role of cellular uptake in the reversal of multidrug resistance by PEG-b-PLA polymeric micelles.
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.
authors.affiliation: National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Xiao
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Xiong
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Sun
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.forename: Huabing
authors.initials: H
authors.lastname: Chen
authors.forename: Lu
authors.initials: L
authors.lastname: Gan
authors.forename: Huibi
authors.initials: H
authors.lastname: Xu
authors.forename: Xiangliang
authors.initials: X
authors.lastname: Yang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D007773:Lactates / Q000737:chemistry* / Q000378:metabolism*; D008422:Materials Testing; D008823:Micelles; D018625:Microscopy, Atomic Force; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000378:metabolism*; D011108:Polymers / Q000737:chemistry / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D007773:Lactates; D008823:Micelles; D011108:Polymers; C088513:poly(lactic acid-ethylene glycol); D011092:Polyethylene Glycols; D017239:Paclitaxel