Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems
The use of dexamethasone for eye disease treatment is limited by its low solubility, bioavailability, and rapid elimination when applied topically. The covalent conjugation of dexamethasone with polymeric carriers is a promising strategy to overcome existing drawbacks. In this work, amphiphilic poly...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/3702 |
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| author | Natalia Zashikhina Sergei Gladnev Vladimir Sharoyko Viktor Korzhikov-Vlakh Evgenia Korzhikova-Vlakh Tatiana Tennikova |
| author_facet | Natalia Zashikhina Sergei Gladnev Vladimir Sharoyko Viktor Korzhikov-Vlakh Evgenia Korzhikova-Vlakh Tatiana Tennikova |
| author_sort | Natalia Zashikhina |
| collection | DOAJ |
| description | The use of dexamethasone for eye disease treatment is limited by its low solubility, bioavailability, and rapid elimination when applied topically. The covalent conjugation of dexamethasone with polymeric carriers is a promising strategy to overcome existing drawbacks. In this work, amphiphilic polypeptides capable of self-assembly into nanoparticles were proposed as potential delivery systems for intravitreal delivery. The nanoparticles were prepared and characterized using poly(L-glutamic acid-co-D-phenylalanine) and poly(L-lysine-co-D/L-phenylalanine) as well as poly(L-lysine-co-D/L-phenylalanine) covered with heparin. The critical association concentration for the polypeptides obtained was in the 4.2–9.4 μg/mL range. The hydrodynamic size of the formed nanoparticles was between 90 and 210 nm, and they had an index of polydispersity between 0.08 and 0.27 and an absolute zeta-potential value between 20 and 45 mV. The ability of nanoparticles to migrate in the vitreous humor was examined using intact porcine vitreous. Conjugation of DEX with polypeptides was performed by additional succinylation of DEX and activation of carboxyl groups introduced to react with primary amines in polypeptides. The structures of all intermediate and final compounds were verified by <sup>1</sup>H NMR spectroscopy. The amount of conjugated DEX can be varied from 6 to 220 µg/mg of polymer. The hydrodynamic diameter of the nanoparticle-based conjugates was increased to 200–370 nm, depending on the polymer sample and drug loading. The release of DEX from the conjugates due to hydrolysis of the ester bond between DEX and the succinyl moiety was studied both in a buffer medium and a vitreous/buffer mixture (50/50, <i>v</i>/<i>v</i>). As expected, the release in the vitreous medium was faster. However, the release rate could be controlled in the range of 96–192 h by varying the polymer composition. In addition, several mathematical models were used to assess the release profiles and figure out how DEX is released. |
| first_indexed | 2024-03-11T08:41:56Z |
| format | Article |
| id | doaj.art-73946ff8e44a438fa192ba19198f4c7c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:41:56Z |
| publishDate | 2023-02-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-73946ff8e44a438fa192ba19198f4c7c2023-11-16T21:03:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244370210.3390/ijms24043702Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery SystemsNatalia Zashikhina0Sergei Gladnev1Vladimir Sharoyko2Viktor Korzhikov-Vlakh3Evgenia Korzhikova-Vlakh4Tatiana Tennikova5Institute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg 199004, RussiaInstitute of Chemistry, Saint-Petersburg State University, St. Petersburg 198504, RussiaInstitute of Chemistry, Saint-Petersburg State University, St. Petersburg 198504, RussiaInstitute of Chemistry, Saint-Petersburg State University, St. Petersburg 198504, RussiaInstitute of Macromolecular Compounds, Russian Academy of Sciences, St. Petersburg 199004, RussiaInstitute of Chemistry, Saint-Petersburg State University, St. Petersburg 198504, RussiaThe use of dexamethasone for eye disease treatment is limited by its low solubility, bioavailability, and rapid elimination when applied topically. The covalent conjugation of dexamethasone with polymeric carriers is a promising strategy to overcome existing drawbacks. In this work, amphiphilic polypeptides capable of self-assembly into nanoparticles were proposed as potential delivery systems for intravitreal delivery. The nanoparticles were prepared and characterized using poly(L-glutamic acid-co-D-phenylalanine) and poly(L-lysine-co-D/L-phenylalanine) as well as poly(L-lysine-co-D/L-phenylalanine) covered with heparin. The critical association concentration for the polypeptides obtained was in the 4.2–9.4 μg/mL range. The hydrodynamic size of the formed nanoparticles was between 90 and 210 nm, and they had an index of polydispersity between 0.08 and 0.27 and an absolute zeta-potential value between 20 and 45 mV. The ability of nanoparticles to migrate in the vitreous humor was examined using intact porcine vitreous. Conjugation of DEX with polypeptides was performed by additional succinylation of DEX and activation of carboxyl groups introduced to react with primary amines in polypeptides. The structures of all intermediate and final compounds were verified by <sup>1</sup>H NMR spectroscopy. The amount of conjugated DEX can be varied from 6 to 220 µg/mg of polymer. The hydrodynamic diameter of the nanoparticle-based conjugates was increased to 200–370 nm, depending on the polymer sample and drug loading. The release of DEX from the conjugates due to hydrolysis of the ester bond between DEX and the succinyl moiety was studied both in a buffer medium and a vitreous/buffer mixture (50/50, <i>v</i>/<i>v</i>). As expected, the release in the vitreous medium was faster. However, the release rate could be controlled in the range of 96–192 h by varying the polymer composition. In addition, several mathematical models were used to assess the release profiles and figure out how DEX is released.https://www.mdpi.com/1422-0067/24/4/3702amphiphilic polypeptidesself-assembled nanoparticlesdexamethasonepolymer-drug conjugatesdrug delivery systemsintravitreal delivery |
| spellingShingle | Natalia Zashikhina Sergei Gladnev Vladimir Sharoyko Viktor Korzhikov-Vlakh Evgenia Korzhikova-Vlakh Tatiana Tennikova Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems International Journal of Molecular Sciences amphiphilic polypeptides self-assembled nanoparticles dexamethasone polymer-drug conjugates drug delivery systems intravitreal delivery |
| title | Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems |
| title_full | Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems |
| title_fullStr | Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems |
| title_full_unstemmed | Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems |
| title_short | Synthesis and Characterization of Nanoparticle-Based Dexamethasone-Polypeptide Conjugates as Potential Intravitreal Delivery Systems |
| title_sort | synthesis and characterization of nanoparticle based dexamethasone polypeptide conjugates as potential intravitreal delivery systems |
| topic | amphiphilic polypeptides self-assembled nanoparticles dexamethasone polymer-drug conjugates drug delivery systems intravitreal delivery |
| url | https://www.mdpi.com/1422-0067/24/4/3702 |
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