Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and Characterization
Cancer is still one of the major diseases worldwide. The discovery of new drugs and the improvement of existing ones is one of the areas of priority in the fight against cancer. Dioxadet ([5-[[4,6-bis(aziridin-1-yl)-1,3,5-triazin-2-yl]amino]-2,2-dimethyl-1,3-dioxan-5-yl]methanol) represents one of t...
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MDPI AG
2022-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/11/2506 |
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| author | Ekaterina Sinitsyna Irina Bagaeva Erik Gandalipov Evgenia Fedotova Viktor Korzhikov-Vlakh Tatiana Tennikova Evgenia Korzhikova-Vlakh |
| author_facet | Ekaterina Sinitsyna Irina Bagaeva Erik Gandalipov Evgenia Fedotova Viktor Korzhikov-Vlakh Tatiana Tennikova Evgenia Korzhikova-Vlakh |
| author_sort | Ekaterina Sinitsyna |
| collection | DOAJ |
| description | Cancer is still one of the major diseases worldwide. The discovery of new drugs and the improvement of existing ones is one of the areas of priority in the fight against cancer. Dioxadet ([5-[[4,6-bis(aziridin-1-yl)-1,3,5-triazin-2-yl]amino]-2,2-dimethyl-1,3-dioxan-5-yl]methanol) represents one of the promising 1,3,5-triazine derivatives and has cytostatic activity towards ovarian cancer. In this study, we first report the development of dioxadet-bearing nanomedicines based on block-copolymers of poly(ethylene glycol) monomethyl ether (mPEG) and poly(D,L-lactic acid) (PLA)/poly(ε-caprolactone) (PCL) and then conduct an investigation into their characteristics and properties. The preparation of narrow-sized nanoparticles with a hydrodynamic diameter of 100–120 nm was optimized using a nanoprecipitation approach. Thoughtful optimization of the preparation of nanomedicines was carried out through adjustments to the polymer’s molecular weight, the pH of the aqueous medium used for nanoprecipitation, the initial drug amount in respect to the polymer, and polymer concentration in the organic phase. Under optimized conditions, spherical-shaped nanomedicines with a hydrodynamic diameter of up to 230 nm (PDI < 0.2) containing up to 592 ± 22 μg of dioxadet per mg of polymer nanoparticles were prepared. Study of the drug’s release in a model medium revealed the release up to 64% and 46% of the drug after 8 days for mPEG-<i>b</i>-PLA and mPEG-<i>b</i>-PCL, respectively. Deep analysis of the release mechanisms was carried out with the use of a number of mathematical models. The developed nanoparticles were non-toxic towards both normal (CHO-K1) and cancer (A2780 and SK-OV-3) ovarian cells. A cell cycle study revealed lesser toxicity of nanomedicines towards normal cells and increased toxicity towards cancer cells. The IC<sub>50</sub> values determined for dioxadet nanoformulations were in the range of 0.47–4.98 μg/mL for cancer cells, which is close to the free drug’s efficacy (2.60–4.14 μg/mL). The highest cytotoxic effect was found for dioxadet loaded to mPEG-<i>b</i>-PCL nanoparticles. |
| first_indexed | 2024-03-09T18:04:01Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T18:04:01Z |
| publishDate | 2022-11-01 |
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| series | Pharmaceutics |
| spelling | doaj.art-704265bb95b44ceeb493fa1cc1ba700f2023-11-24T09:36:58ZengMDPI AGPharmaceutics1999-49232022-11-011411250610.3390/pharmaceutics14112506Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and CharacterizationEkaterina Sinitsyna0Irina Bagaeva1Erik Gandalipov2Evgenia Fedotova3Viktor Korzhikov-Vlakh4Tatiana Tennikova5Evgenia Korzhikova-Vlakh6Institute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoy pr. 31, St. Petersburg 199004, RussiaInstitute of Chemistry, Saint-Petersburg State University, Universitetsky pr. 26, St. Petersburg 198504, RussiaInternational Institute of Solution Chemistry and Advanced Materials Technologies, ITMO University, Lomonosov Street 9, St. Petersburg 191002, RussiaInstitute of Chemistry, Saint-Petersburg State University, Universitetsky pr. 26, St. Petersburg 198504, RussiaInstitute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoy pr. 31, St. Petersburg 199004, RussiaInstitute of Chemistry, Saint-Petersburg State University, Universitetsky pr. 26, St. Petersburg 198504, RussiaInstitute of Macromolecular Compounds, Russian Academy of Sciences, Bolshoy pr. 31, St. Petersburg 199004, RussiaCancer is still one of the major diseases worldwide. The discovery of new drugs and the improvement of existing ones is one of the areas of priority in the fight against cancer. Dioxadet ([5-[[4,6-bis(aziridin-1-yl)-1,3,5-triazin-2-yl]amino]-2,2-dimethyl-1,3-dioxan-5-yl]methanol) represents one of the promising 1,3,5-triazine derivatives and has cytostatic activity towards ovarian cancer. In this study, we first report the development of dioxadet-bearing nanomedicines based on block-copolymers of poly(ethylene glycol) monomethyl ether (mPEG) and poly(D,L-lactic acid) (PLA)/poly(ε-caprolactone) (PCL) and then conduct an investigation into their characteristics and properties. The preparation of narrow-sized nanoparticles with a hydrodynamic diameter of 100–120 nm was optimized using a nanoprecipitation approach. Thoughtful optimization of the preparation of nanomedicines was carried out through adjustments to the polymer’s molecular weight, the pH of the aqueous medium used for nanoprecipitation, the initial drug amount in respect to the polymer, and polymer concentration in the organic phase. Under optimized conditions, spherical-shaped nanomedicines with a hydrodynamic diameter of up to 230 nm (PDI < 0.2) containing up to 592 ± 22 μg of dioxadet per mg of polymer nanoparticles were prepared. Study of the drug’s release in a model medium revealed the release up to 64% and 46% of the drug after 8 days for mPEG-<i>b</i>-PLA and mPEG-<i>b</i>-PCL, respectively. Deep analysis of the release mechanisms was carried out with the use of a number of mathematical models. The developed nanoparticles were non-toxic towards both normal (CHO-K1) and cancer (A2780 and SK-OV-3) ovarian cells. A cell cycle study revealed lesser toxicity of nanomedicines towards normal cells and increased toxicity towards cancer cells. The IC<sub>50</sub> values determined for dioxadet nanoformulations were in the range of 0.47–4.98 μg/mL for cancer cells, which is close to the free drug’s efficacy (2.60–4.14 μg/mL). The highest cytotoxic effect was found for dioxadet loaded to mPEG-<i>b</i>-PCL nanoparticles.https://www.mdpi.com/1999-4923/14/11/25061,3,5-triazine derivativesdioxadetnanomedicinesanticancer drugspolymer nanoparticlesnanoprecipitation |
| spellingShingle | Ekaterina Sinitsyna Irina Bagaeva Erik Gandalipov Evgenia Fedotova Viktor Korzhikov-Vlakh Tatiana Tennikova Evgenia Korzhikova-Vlakh Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and Characterization Pharmaceutics 1,3,5-triazine derivatives dioxadet nanomedicines anticancer drugs polymer nanoparticles nanoprecipitation |
| title | Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and Characterization |
| title_full | Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and Characterization |
| title_fullStr | Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and Characterization |
| title_full_unstemmed | Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and Characterization |
| title_short | Nanomedicines Bearing an Alkylating Cytostatic Drug from the Group of 1,3,5-Triazine Derivatives: Development and Characterization |
| title_sort | nanomedicines bearing an alkylating cytostatic drug from the group of 1 3 5 triazine derivatives development and characterization |
| topic | 1,3,5-triazine derivatives dioxadet nanomedicines anticancer drugs polymer nanoparticles nanoprecipitation |
| url | https://www.mdpi.com/1999-4923/14/11/2506 |
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