Cellular uptake, intracellular trafficking, and antitumor efficacy of doxorubicin-loaded reduction-sensitive micelles
Abstract
Reduction-sensitive micelles were prepared from monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16), an amphiphilic poly(ethylene glycol) derivative containing a disulfide bond. The micelles were then used for the intracellular delivery of the anticancer drug doxorubicin (DOX) into tumor cells, and the cellular uptake mechanisms of the micelles were determined. To serve as a control, monomethoxy-poly(ethylene glycol)-C-C-hexadecyl (mPEG-C-C-C16) with an analogous structure but without a disulfide bond was also prepared. The polymer could self-assemble into micelles in an aqueous solution and be loaded with high-content DOX. In vitro release studies revealed that DOX-loaded mPEG-S-S-C16 micelles released DOX faster than DOX-loaded mPEG-C-C-C16 micelles in the presence of dithiothreitol (DTT), but showed similar release rates in the absence of DTT. MTT assay demonstrated significantly enhanced cytotoxicity of DOX-loaded mPEG-S-S-C16 micelles against the human cervical cancer cells (HeLa) compared with DOX-loaded mPEG-C-C-C16 micelles, but there was no significant difference in the cytotoxicity between the two DOX-loaded micelles against the african green monkey SV40-transformed kidney fibroblast cells (COS-7). Confocal laser scanning microscopy observation and flow cytometry analyses indicated that DOX-loaded mPEG-S-S-C16 micelles were efficiently internalized into HeLa cells, released DOX into the cytoplasm, and entered the nuclei. By contrast, in the case of DOX-loaded mPEG-C-C-C16 micelles, little DOX was found in the nuclei. Endocytosis inhibition results proved that both mPEG-S-S-C16 and mPEG-C-C-C16 micelles entered the HeLa cells mainly through the clathrin-mediated endocytosis pathway, and caveolae-mediated endocytosis was involved to a small extent. These results indicated that the different behaviors of cell uptake between reduction-sensitive and -insensitive micelles may occur after the micelles were internalized into the cells, but not during endocytosis, and the potential of this reduction-sensitive polymer for the effective intracellular delivery of anticancer drugs.
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Images highlight the presence of FRET signal outside the cells for both types of micelles, an intense green fluorescence (due to DiO emission) in the plasma membrane only in the case of mPEG-PDLLA micelles, and for both mPEG-PDLLA and disulfide bonded micelles a yellow fluorescence inside cells, originated from the overlap between red (DiI) and green signal (DiO), testifying the presence of both探头
“The resulting images (Fig. 12) highlight the presence of FRET signal outside the cells for both type of micelles, an intense green fluorescence (due to DiO emission) in the plasma membrane only in the case of mPEG-PDLLA micelles, and for both mPEG-PDLLA and disulfide bonded micelles a yellow fluorescence inside cells, originated from the overlap between red (DiI) and green signal (DiO), that test”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [92]
Lee et al. investigated the impact of micelles' stability in cellular internalization pathway by comparing self-assembled mPEG-PDLLA micelles with disulfide-stabilized mPEG-(Cys)4-PDLLA micelles.
“Another study was carried out by Lee et al. [92] in order to investigate the impact of micelles' stability in cellular internalization pathway.With this aim, they compared self-assembled micelles made of mPEG-PDLLA with micelles stabilized by disulfide bonds and made by mPEG-(Cys)4-PDLLA.”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [92]
Integrated with data on endocytic trafficking, different drug delivery mechanisms have been demonstrated: self-assembled mPEG-PDLLA micelles, intact in the extracellular space, dissociated following micelle-membrane interactions, and the hydrophobic probe DiO accumulated in the plasma membrane; alternatively, disulfide bonded mPEG-(Cys)4-PDLLA micelles were internalized via endocytic pathways and,
“Thanks to these results, integrated with data on endocytic trafficking, different drug delivery mechanisms have been demonstrated: self-assembled micelles (mPEG-PDLLA), that are intact in the extracellular space, dissociated following micelle-membrane interactions, and the hydrophobic probe (DiO) accumulated in the plasma membrane.Alternatively, disulfide bonded micelles (mPEG-(Cys)4-PDLLA) were”
From Polymeric micelles in drug delivery: An insight of the techniques for their characterization and assessment in biorelevant conditions (2021) · cites this paper as [92]
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Ghezzi, M., Pescina, S., Padula, C., Santi, P., Del Favero, E., Cantù, L., & Nicoli, S. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.02.031 · Cited by 1,135 · see citing works
Gaspar, V. M., Gonçalves, C., de Melo-Diogo, D., Costa, E. C., Queiroz, J. A., Pichon, C., Sousa, F., & Correia, I. J. (2014) · Journal of Controlled Release · doi:10.1016/j.jconrel.2014.06.040 · Cited by 91 · see citing works
- Authors
- Cui, C., Xue, Y.-N., Wu, M., Zhang, Y., Yu, P., Liu, L., Zhuo, R.-X., & Huang, S.-W.
- Affiliations
- Wuhan University (CN)
- Corresponding author
- Huang, Shi-Wen
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2013-05
- Volume
- 34
- Issue
- 15
- Pages
- 3858-3869
- ISSN
- 0142-9612 (ISSN-L)
- OpenAlex
- W1977353373
- Cited by
- 169
- References
- 0
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 10 · 2022: 8 · 2021: 5 · 2020: 12 · 2019: 14 · 2018: 19 · 2017: 20 · 2016: 23 · 2015: 26 · 2014: 12 · 2013: 3
- FWCI
- 8.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Basic Research Program of China (2009CB930300, 2011CB606202)
- National Natural Science Foundation of China (21074101, 51273150)
- Program for Changjiang Scholars and Innovative Research Team in University (IRT1030)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- doxorubicin, intracellular drug delivery, cellular uptake, intracellular trafficking, disulfide bonds, clathrin-mediated endocytosis, caveolae-mediated endocytosis, drug release, HeLa cells, cervical cancer, antitumor efficacy, anticancer drug delivery
- MeSH terms
- Animals, Antineoplastic Agents, Biological Transport, Chlorocebus aethiops, Doxorubicin, Endocytosis, Flow Cytometry, HeLa Cells, Humans, Light, Micelles, Magnetic Resonance Spectroscopy, Oxidation-Reduction, Particle Size, Polyethylene Glycols, Scattering, Radiation, Surface-Active Agents, Treatment Outcome, Cell Death, Microscopy, Confocal, COS Cells, Intracellular Space, Microscopy, Electron, Transmission
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