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.
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AFM has also been proposed as an innovative tool for studying the mechanisms regulating nanocarrier interaction with cell membrane and their internalization.
“AFM has also been proposed as innovative tool for studying the mechanisms regulating nanocarrier interaction with cell membrane and their internalization, which are quite relevant for ensuring effective drug delivery to the target [161][162][163].”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [161]
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- Authors
- Xiao, L., Xiong, X., Sun, X., Zhu, Y., Yang, H., Chen, H., Gan, L., Xu, H., & Yang, X.
- Affiliations
- Huazhong University of Science and Technology (CN)
- Corresponding author
- Gan, Lu
- Yang, Xiangliang
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 32
- Issue
- 22
- Pages
- 5148-5157
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W1984677400
- Cited by
- 169
- References
- 37
- Citations by year
- 2025: 7 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 9 · 2020: 12 · 2019: 9 · 2018: 13 · 2017: 16 · 2016: 17 · 2015: 15 · 2014: 22 · 2013: 19 · 2012: 15
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (30873121)
- National Key Research and Development Program of China (2007CB935800, 2010CB934000)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- multidrug resistance reversal, P-glycoprotein inhibition, paclitaxel, cellular uptake, endocytosis, caveolae, lipid rafts, membrane microenvironment, membrane depolarization, membrane microviscosity, apoptosis, PARP cleavage, ovarian cancer cells, nano-drug delivery
- MeSH terms
- Antineoplastic Agents, Phytogenic, Cell Membrane, Drug Carriers, Endocytosis, Humans, Lactates, Materials Testing, Micelles, Particle Size, Polyethylene Glycols, Polymers, Apoptosis, Paclitaxel, Drug Resistance, Multiple, Microscopy, Atomic Force, ATP Binding Cassette Transporter, Subfamily B, Member 1, Fluorescence Resonance Energy Transfer, Cell Line, Tumor
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