Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells
Nanoparticle-based chemotherapy is considered to be an effective approach to cancer diagnostics and therapy in modern biomedicine. However, efficient tumor targeting remains a great challenge due to the lack of specificity, selectivity, and high dosage of chemotherapeutic drugs required. A two-step...
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| Format: | Article |
| Language: | English |
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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/1999-4923/15/1/52 |
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| author | Elena N. Komedchikova Olga A. Kolesnikova Ekaterina D. Tereshina Polina A. Kotelnikova Anna S. Sogomonyan Alexey V. Stepanov Sergey M. Deyev Maxim P. Nikitin Victoria O. Shipunova |
| author_facet | Elena N. Komedchikova Olga A. Kolesnikova Ekaterina D. Tereshina Polina A. Kotelnikova Anna S. Sogomonyan Alexey V. Stepanov Sergey M. Deyev Maxim P. Nikitin Victoria O. Shipunova |
| author_sort | Elena N. Komedchikova |
| collection | DOAJ |
| description | Nanoparticle-based chemotherapy is considered to be an effective approach to cancer diagnostics and therapy in modern biomedicine. However, efficient tumor targeting remains a great challenge due to the lack of specificity, selectivity, and high dosage of chemotherapeutic drugs required. A two-step targeted drug delivery strategy (DDS), involving cancer cell pre-targeting, first with a first nontoxic module and subsequent targeting with a second complementary toxic module, is a solution for decreasing doses for administration and lowering systemic toxicity. To prove two-step DDS efficiency, we performed a direct comparison of one-step and two-step DDS based on chemotherapy loaded PLGA nanoparticles and barnase*barstar interface. Namely, we developed and thoroughly characterized the two-step targeting strategy of HER2-overexpressing cancer cells. The first targeting block consists of anti-HER2 scaffold polypeptide DARPin9_29 fused with barstar. Barstar exhibits an extremely effective binding to ribonuclease barnase with K<sub>aff</sub> = 10<sup>14</sup> M<sup>−1</sup>, thus making the barnase*barstar protein pair one of the strongest known protein*protein complexes. A therapeutic PLGA-based nanocarrier coupled to barnase was used as a second targeting block. The PLGA nanoparticles were loaded with diagnostic dye, Nile Blue, and a chemotherapeutic drug, doxorubicin. We showed that the two-step DDS increases the performance of chemotherapy-loaded nanocarriers: IC50 of doxorubicin delivered via two-step DDS was more than 100 times lower than that for one-step DDS: IC50 = 43 ± 3 nM for two-step DDS vs. IC50 = 4972 ± 1965 nM for one-step DDS. The obtained results demonstrate the significant efficiency of two-step DDS over the classical one-step one. We believe that the obtained data will significantly change the direction of research in developing targeted anti-cancer drugs and promote the creation of new generation cancer treatment strategies. |
| first_indexed | 2024-03-09T11:28:34Z |
| format | Article |
| id | doaj.art-80f4fa589040416cab70d976f6ed3e28 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T11:28:34Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-80f4fa589040416cab70d976f6ed3e282023-11-30T23:57:00ZengMDPI AGPharmaceutics1999-49232022-12-011515210.3390/pharmaceutics15010052Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing CellsElena N. Komedchikova0Olga A. Kolesnikova1Ekaterina D. Tereshina2Polina A. Kotelnikova3Anna S. Sogomonyan4Alexey V. Stepanov5Sergey M. Deyev6Maxim P. Nikitin7Victoria O. Shipunova8Moscow Institute of Physics and Technology, 141701 Dolgoprudny, RussiaMoscow Institute of Physics and Technology, 141701 Dolgoprudny, RussiaMoscow Institute of Physics and Technology, 141701 Dolgoprudny, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaShemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, RussiaMoscow Institute of Physics and Technology, 141701 Dolgoprudny, RussiaMoscow Institute of Physics and Technology, 141701 Dolgoprudny, RussiaNanoparticle-based chemotherapy is considered to be an effective approach to cancer diagnostics and therapy in modern biomedicine. However, efficient tumor targeting remains a great challenge due to the lack of specificity, selectivity, and high dosage of chemotherapeutic drugs required. A two-step targeted drug delivery strategy (DDS), involving cancer cell pre-targeting, first with a first nontoxic module and subsequent targeting with a second complementary toxic module, is a solution for decreasing doses for administration and lowering systemic toxicity. To prove two-step DDS efficiency, we performed a direct comparison of one-step and two-step DDS based on chemotherapy loaded PLGA nanoparticles and barnase*barstar interface. Namely, we developed and thoroughly characterized the two-step targeting strategy of HER2-overexpressing cancer cells. The first targeting block consists of anti-HER2 scaffold polypeptide DARPin9_29 fused with barstar. Barstar exhibits an extremely effective binding to ribonuclease barnase with K<sub>aff</sub> = 10<sup>14</sup> M<sup>−1</sup>, thus making the barnase*barstar protein pair one of the strongest known protein*protein complexes. A therapeutic PLGA-based nanocarrier coupled to barnase was used as a second targeting block. The PLGA nanoparticles were loaded with diagnostic dye, Nile Blue, and a chemotherapeutic drug, doxorubicin. We showed that the two-step DDS increases the performance of chemotherapy-loaded nanocarriers: IC50 of doxorubicin delivered via two-step DDS was more than 100 times lower than that for one-step DDS: IC50 = 43 ± 3 nM for two-step DDS vs. IC50 = 4972 ± 1965 nM for one-step DDS. The obtained results demonstrate the significant efficiency of two-step DDS over the classical one-step one. We believe that the obtained data will significantly change the direction of research in developing targeted anti-cancer drugs and promote the creation of new generation cancer treatment strategies.https://www.mdpi.com/1999-4923/15/1/52HER2targeted chemotherapyscaffold proteinsDARPinPLGApolymer particles |
| spellingShingle | Elena N. Komedchikova Olga A. Kolesnikova Ekaterina D. Tereshina Polina A. Kotelnikova Anna S. Sogomonyan Alexey V. Stepanov Sergey M. Deyev Maxim P. Nikitin Victoria O. Shipunova Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells Pharmaceutics HER2 targeted chemotherapy scaffold proteins DARPin PLGA polymer particles |
| title | Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells |
| title_full | Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells |
| title_fullStr | Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells |
| title_full_unstemmed | Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells |
| title_short | Two-Step Targeted Drug Delivery via Proteinaceous Barnase-Barstar Interface and Doxorubicin-Loaded Nano-PLGA Outperforms One-Step Strategy for Targeted Delivery to HER2-Overexpressing Cells |
| title_sort | two step targeted drug delivery via proteinaceous barnase barstar interface and doxorubicin loaded nano plga outperforms one step strategy for targeted delivery to her2 overexpressing cells |
| topic | HER2 targeted chemotherapy scaffold proteins DARPin PLGA polymer particles |
| url | https://www.mdpi.com/1999-4923/15/1/52 |
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