Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis Treatment
Reactive oxygen species (ROS) are essential signaling molecules that maintain intracellular redox balance; however, the overproduction of ROS often causes dysfunction in redox homeostasis and induces serious diseases. Antioxidants are crucial candidates for reducing overproduced ROS; however, most a...
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MDPI AG
2023-06-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/6/1775 |
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| author | Yuta Koda Yukio Nagasaki |
| author_facet | Yuta Koda Yukio Nagasaki |
| author_sort | Yuta Koda |
| collection | DOAJ |
| description | Reactive oxygen species (ROS) are essential signaling molecules that maintain intracellular redox balance; however, the overproduction of ROS often causes dysfunction in redox homeostasis and induces serious diseases. Antioxidants are crucial candidates for reducing overproduced ROS; however, most antioxidants are less effective than anticipated. Therefore, we designed new polymer-based antioxidants based on the natural amino acid, cysteine (Cys). Amphiphilic block copolymers, composed of a hydrophilic poly(ethylene glycol) (PEG) segment and a hydrophobic poly(cysteine) (PCys) segment, were synthesized. In the PCys segment, the free thiol groups in the side chain were protected by thioester moiety. The obtained block copolymers formed self-assembling nanoparticles (Nano<sup>Cys(Bu)</sup>) in water, and the hydrodynamic diameter was 40–160 nm, as determined by dynamic light scattering (DLS) measurements. Nano<sup>Cys(Bu)</sup> was stable from pH 2 to 8 under aqueous conditions, as confirmed by the hydrodynamic diameter of Nano<sup>Cys(Bu)</sup>. Finally, Nano<sup>Cys(Bu)</sup> was applied to sepsis treatment to investigate the potential of Nano<sup>Cys(Bu)</sup>. Nano<sup>Cys(Bu)</sup> was supplied to BALB/cA mice by free drinking for two days, and lipopolysaccharide (LPS) was intraperitoneally injected into the mice to prepare a sepsis shock model (LPS = 5 mg per kg body weight (BW)). Compared with the Cys and no-treatment groups, Nano<sup>Cys(Bu)</sup> prolonged the half-life by five to six hours. Nano<sup>Cys(Bu)</sup>, designed in this study, shows promise as a candidate for enhancing antioxidative efficacy and mitigating the adverse effect of cysteine. |
| first_indexed | 2024-03-11T02:02:30Z |
| format | Article |
| id | doaj.art-c2e09310cfe242f88baee8af5e009fdc |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T02:02:30Z |
| publishDate | 2023-06-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-c2e09310cfe242f88baee8af5e009fdc2023-11-18T12:06:22ZengMDPI AGPharmaceutics1999-49232023-06-01156177510.3390/pharmaceutics15061775Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis TreatmentYuta Koda0Yukio Nagasaki1Department of Materials Science, Faculty of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba 305-8573, JapanDepartment of Materials Science, Faculty of Pure and Applied Sciences, University of Tsukuba, Tennoudai 1-1-1, Tsukuba 305-8573, JapanReactive oxygen species (ROS) are essential signaling molecules that maintain intracellular redox balance; however, the overproduction of ROS often causes dysfunction in redox homeostasis and induces serious diseases. Antioxidants are crucial candidates for reducing overproduced ROS; however, most antioxidants are less effective than anticipated. Therefore, we designed new polymer-based antioxidants based on the natural amino acid, cysteine (Cys). Amphiphilic block copolymers, composed of a hydrophilic poly(ethylene glycol) (PEG) segment and a hydrophobic poly(cysteine) (PCys) segment, were synthesized. In the PCys segment, the free thiol groups in the side chain were protected by thioester moiety. The obtained block copolymers formed self-assembling nanoparticles (Nano<sup>Cys(Bu)</sup>) in water, and the hydrodynamic diameter was 40–160 nm, as determined by dynamic light scattering (DLS) measurements. Nano<sup>Cys(Bu)</sup> was stable from pH 2 to 8 under aqueous conditions, as confirmed by the hydrodynamic diameter of Nano<sup>Cys(Bu)</sup>. Finally, Nano<sup>Cys(Bu)</sup> was applied to sepsis treatment to investigate the potential of Nano<sup>Cys(Bu)</sup>. Nano<sup>Cys(Bu)</sup> was supplied to BALB/cA mice by free drinking for two days, and lipopolysaccharide (LPS) was intraperitoneally injected into the mice to prepare a sepsis shock model (LPS = 5 mg per kg body weight (BW)). Compared with the Cys and no-treatment groups, Nano<sup>Cys(Bu)</sup> prolonged the half-life by five to six hours. Nano<sup>Cys(Bu)</sup>, designed in this study, shows promise as a candidate for enhancing antioxidative efficacy and mitigating the adverse effect of cysteine.https://www.mdpi.com/1999-4923/15/6/1775PEG-<i>block</i>-poly(cysteine)block copolymerssepsisoxidative stressreactive oxygen species (ROS)nanoparticle antioxidants |
| spellingShingle | Yuta Koda Yukio Nagasaki Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis Treatment Pharmaceutics PEG-<i>block</i>-poly(cysteine) block copolymers sepsis oxidative stress reactive oxygen species (ROS) nanoparticle antioxidants |
| title | Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis Treatment |
| title_full | Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis Treatment |
| title_fullStr | Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis Treatment |
| title_full_unstemmed | Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis Treatment |
| title_short | Newly Designed Cysteine-Based Self-Assembling Prodrugs for Sepsis Treatment |
| title_sort | newly designed cysteine based self assembling prodrugs for sepsis treatment |
| topic | PEG-<i>block</i>-poly(cysteine) block copolymers sepsis oxidative stress reactive oxygen species (ROS) nanoparticle antioxidants |
| url | https://www.mdpi.com/1999-4923/15/6/1775 |
| work_keys_str_mv | AT yutakoda newlydesignedcysteinebasedselfassemblingprodrugsforsepsistreatment AT yukionagasaki newlydesignedcysteinebasedselfassemblingprodrugsforsepsistreatment |