Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application
In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)<sub>2k</sub>-<i>b</i>-poly(furfuryl methacrylate)<sub>1.5k</sub> (PEO<sub>2k</sub>-<i>b</i>-...
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MDPI AG
2023-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/4/1159 |
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| author | Sonyabapu Yadav Kalyan Ramesh Obireddy Sreekanth Reddy Viswanathan Karthika Parveen Kumar Sung-Han Jo Seong II Yoo Sang-Hyug Park Kwon Taek Lim |
| author_facet | Sonyabapu Yadav Kalyan Ramesh Obireddy Sreekanth Reddy Viswanathan Karthika Parveen Kumar Sung-Han Jo Seong II Yoo Sang-Hyug Park Kwon Taek Lim |
| author_sort | Sonyabapu Yadav |
| collection | DOAJ |
| description | In this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)<sub>2k</sub>-<i>b</i>-poly(furfuryl methacrylate)<sub>1.5k</sub> (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub> from FMA monomers and PEO<sub>2k</sub>-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels–Alder reaction. Under physiological conditions, the structural stability of both S–S and Se–Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S–S and Se–Se bonds. In contrast, the S–S bond was intact in the presence of 100 mM H<sub>2</sub>O<sub>2,</sub> while the Se–Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-Se)<sub>2</sub> micelles varied more significantly in response to changes in the redox environment than (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-S)<sub>2</sub> micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S–S/Se–Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k-</sub>Se)<sub>2</sub> micelles can be more sensitive drug carriers than (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-S)<sub>2</sub> micelles. |
| first_indexed | 2024-03-11T04:37:58Z |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T04:37:58Z |
| publishDate | 2023-04-01 |
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| spelling | doaj.art-1ba716d0d5534c94b01c1d454a0fed2e2023-11-17T20:53:34ZengMDPI AGPharmaceutics1999-49232023-04-01154115910.3390/pharmaceutics15041159Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery ApplicationSonyabapu Yadav0Kalyan Ramesh1Obireddy Sreekanth Reddy2Viswanathan Karthika3Parveen Kumar4Sung-Han Jo5Seong II Yoo6Sang-Hyug Park7Kwon Taek Lim8Department of Smart Green Technology Engineering, Pukyong National University, Busan 48513, Republic of KoreaR&D Center, Devens Lab, SEQENS (CDMO) Pharmaceutical Solutions, Devens, MA 01434, USAMajor of Display Semiconductor Engineering, Pukyong National University, Busan 48513, Republic of KoreaMajor of Display Semiconductor Engineering, Pukyong National University, Busan 48513, Republic of KoreaMajor of Display Semiconductor Engineering, Pukyong National University, Busan 48513, Republic of KoreaDepartment of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of KoreaDepartment of Polymer Engineering, Pukyong National University, Busan 48513, Republic of KoreaDepartment of Biomedical Engineering, Pukyong National University, Busan 48513, Republic of KoreaDepartment of Smart Green Technology Engineering, Pukyong National University, Busan 48513, Republic of KoreaIn this study, diselenide (Se–Se) and disulfide (S–S) redox-responsive core-cross-linked (CCL) micelles were synthesized using poly(ethylene oxide)<sub>2k</sub>-<i>b</i>-poly(furfuryl methacrylate)<sub>1.5k</sub> (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>), and their redox sensitivity was compared. A single electron transfer-living radical polymerization technique was used to prepare PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub> from FMA monomers and PEO<sub>2k</sub>-Br initiators. An anti-cancer drug, doxorubicin (DOX), was incorporated into PFMA hydrophobic parts of the polymeric micelles, which were then cross-linked with maleimide cross-linkers, 1,6-bis(maleimide) hexane, dithiobis(maleimido) ethane and diselenobis(maleimido) ethane via Diels–Alder reaction. Under physiological conditions, the structural stability of both S–S and Se–Se CCL micelles was maintained; however, treatments with 10 mM GSH induced redox-responsive de-cross-linking of S–S and Se–Se bonds. In contrast, the S–S bond was intact in the presence of 100 mM H<sub>2</sub>O<sub>2,</sub> while the Se–Se bond underwent de-crosslinking upon the treatment. DLS studies revealed that the size and PDI of (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-Se)<sub>2</sub> micelles varied more significantly in response to changes in the redox environment than (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-S)<sub>2</sub> micelles. In vitro release studies showed that the developed micelles had a lower drug release rate at pH 7.4, whereas a higher release was observed at pH 5.0 (tumor environment). The micelles were non-toxic against HEK-293 normal cells, which revealed that they could be safe for use. Nevertheless, DOX-loaded S–S/Se–Se CCL micelles exhibited potent cytotoxicity against BT-20 cancer cells. Based on these results, the (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k-</sub>Se)<sub>2</sub> micelles can be more sensitive drug carriers than (PEO<sub>2k</sub>-<i>b</i>-PFMA<sub>1.5k</sub>-S)<sub>2</sub> micelles.https://www.mdpi.com/1999-4923/15/4/1159Diels–Alder reactiondisulfidediselenidecore-cross-linked micellesredox-responsivedrug delivery |
| spellingShingle | Sonyabapu Yadav Kalyan Ramesh Obireddy Sreekanth Reddy Viswanathan Karthika Parveen Kumar Sung-Han Jo Seong II Yoo Sang-Hyug Park Kwon Taek Lim Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application Pharmaceutics Diels–Alder reaction disulfide diselenide core-cross-linked micelles redox-responsive drug delivery |
| title | Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application |
| title_full | Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application |
| title_fullStr | Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application |
| title_full_unstemmed | Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application |
| title_short | Redox-Responsive Comparison of Diselenide and Disulfide Core-Cross-Linked Micelles for Drug Delivery Application |
| title_sort | redox responsive comparison of diselenide and disulfide core cross linked micelles for drug delivery application |
| topic | Diels–Alder reaction disulfide diselenide core-cross-linked micelles redox-responsive drug delivery |
| url | https://www.mdpi.com/1999-4923/15/4/1159 |
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