Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines
Redox-responsive and magnetic nanomaterials are widely used in tumor treatment separately, and while the application of their combined functionalities is perspective, exactly how such synergistic effects can be implemented is still unclear. This report investigates the internalization dynamics of ma...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/1/127 |
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| author | Timur R. Nizamov Artem R. Iliasov Stepan S. Vodopyanov Irina V. Kozhina Igor G. Bordyuzhin Dmitry G. Zhukov Anna V. Ivanova Elizaveta S. Permyakova Pavel S. Mogilnikov Daniil A. Vishnevskiy Igor V. Shchetinin Maxim A. Abakumov Alexander G. Savchenko |
| author_facet | Timur R. Nizamov Artem R. Iliasov Stepan S. Vodopyanov Irina V. Kozhina Igor G. Bordyuzhin Dmitry G. Zhukov Anna V. Ivanova Elizaveta S. Permyakova Pavel S. Mogilnikov Daniil A. Vishnevskiy Igor V. Shchetinin Maxim A. Abakumov Alexander G. Savchenko |
| author_sort | Timur R. Nizamov |
| collection | DOAJ |
| description | Redox-responsive and magnetic nanomaterials are widely used in tumor treatment separately, and while the application of their combined functionalities is perspective, exactly how such synergistic effects can be implemented is still unclear. This report investigates the internalization dynamics of magnetic redox-responsive nanoparticles (MNP-SS) and their cytotoxicity toward PC-3 and 4T1 cell lines. It is shown that MNP-SS synthesized by covalent grafting of polyethylene glycol (PEG) on the magnetic nanoparticle (MNP) surface via SS-bonds lose their colloidal stability and aggregate fully in a solution containing DTT, and partially in conditioned media, whereas the PEGylated MNP (MNP-PEG) without S-S linker control remains stable under the same conditions. Internalized MNP-SS lose the PEG shell more quickly, causing enhanced magnetic core dissolution and thus increased toxicity. This was confirmed by fluorescence microscopy using MNP-SS dual-labeled by Cy3 via labile disulfide, and Cy5 via a rigid linker. The dyes demonstrated a significant difference in fluorescence dynamics and intensity. Additionally, MNP-SS demonstrate quicker cellular uptake compared to MNP-PEG, as confirmed by TEM analysis. The combination of disulfide bonds, leading to faster dissolution of the iron oxide core, and the high-oxidative potential Fe<sup>3+</sup> ions can synergically enhance oxidative stress in comparison with more stable coating without SS-bonds in the case of MNP-PEG. It decreases the cancer cell viability, especially for the 4T1, which is known for being sensitive to ferroptosis-triggering factors. In this work, we have shown the effect of redox-responsive grafting of the MNP surface as a key factor affecting MNP-internalization rate and dissolution with the release of iron ions inside cancer cells. This kind of synergistic effect is described for the first time and can be used not only in combination with drug delivery, but also in treatment of tumors responsive to ferroptosis. |
| first_indexed | 2024-03-09T11:27:35Z |
| format | Article |
| id | doaj.art-72d19e92440e4bc8bb26c8c976350fd7 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T11:27:35Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-72d19e92440e4bc8bb26c8c976350fd72023-11-30T23:58:04ZengMDPI AGPharmaceutics1999-49232022-12-0115112710.3390/pharmaceutics15010127Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell LinesTimur R. Nizamov0Artem R. Iliasov1Stepan S. Vodopyanov2Irina V. Kozhina3Igor G. Bordyuzhin4Dmitry G. Zhukov5Anna V. Ivanova6Elizaveta S. Permyakova7Pavel S. Mogilnikov8Daniil A. Vishnevskiy9Igor V. Shchetinin10Maxim A. Abakumov11Alexander G. Savchenko12Department of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Medical Nanobiotechnology, N.I. Pirogov Russian National Research Medical University, Moscow 117997, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaDepartment of Physical Materials Science, National University of Science and Technology (MISIS), Moscow 119049, RussiaRedox-responsive and magnetic nanomaterials are widely used in tumor treatment separately, and while the application of their combined functionalities is perspective, exactly how such synergistic effects can be implemented is still unclear. This report investigates the internalization dynamics of magnetic redox-responsive nanoparticles (MNP-SS) and their cytotoxicity toward PC-3 and 4T1 cell lines. It is shown that MNP-SS synthesized by covalent grafting of polyethylene glycol (PEG) on the magnetic nanoparticle (MNP) surface via SS-bonds lose their colloidal stability and aggregate fully in a solution containing DTT, and partially in conditioned media, whereas the PEGylated MNP (MNP-PEG) without S-S linker control remains stable under the same conditions. Internalized MNP-SS lose the PEG shell more quickly, causing enhanced magnetic core dissolution and thus increased toxicity. This was confirmed by fluorescence microscopy using MNP-SS dual-labeled by Cy3 via labile disulfide, and Cy5 via a rigid linker. The dyes demonstrated a significant difference in fluorescence dynamics and intensity. Additionally, MNP-SS demonstrate quicker cellular uptake compared to MNP-PEG, as confirmed by TEM analysis. The combination of disulfide bonds, leading to faster dissolution of the iron oxide core, and the high-oxidative potential Fe<sup>3+</sup> ions can synergically enhance oxidative stress in comparison with more stable coating without SS-bonds in the case of MNP-PEG. It decreases the cancer cell viability, especially for the 4T1, which is known for being sensitive to ferroptosis-triggering factors. In this work, we have shown the effect of redox-responsive grafting of the MNP surface as a key factor affecting MNP-internalization rate and dissolution with the release of iron ions inside cancer cells. This kind of synergistic effect is described for the first time and can be used not only in combination with drug delivery, but also in treatment of tumors responsive to ferroptosis.https://www.mdpi.com/1999-4923/15/1/127magnetic nanoparticlesredox-responsive materialsdisulfidescytotoxicitytumor cells |
| spellingShingle | Timur R. Nizamov Artem R. Iliasov Stepan S. Vodopyanov Irina V. Kozhina Igor G. Bordyuzhin Dmitry G. Zhukov Anna V. Ivanova Elizaveta S. Permyakova Pavel S. Mogilnikov Daniil A. Vishnevskiy Igor V. Shchetinin Maxim A. Abakumov Alexander G. Savchenko Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines Pharmaceutics magnetic nanoparticles redox-responsive materials disulfides cytotoxicity tumor cells |
| title | Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines |
| title_full | Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines |
| title_fullStr | Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines |
| title_full_unstemmed | Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines |
| title_short | Study of Cytotoxicity and Internalization of Redox-Responsive Iron Oxide Nanoparticles on PC-3 and 4T1 Cancer Cell Lines |
| title_sort | study of cytotoxicity and internalization of redox responsive iron oxide nanoparticles on pc 3 and 4t1 cancer cell lines |
| topic | magnetic nanoparticles redox-responsive materials disulfides cytotoxicity tumor cells |
| url | https://www.mdpi.com/1999-4923/15/1/127 |
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