Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment?
Based on their drug delivery properties and activity against tumors, we combined PAMAM dendrimers with various platinum(IV) complexes in order to provide an improved approach of anticancer treatment. Platinum(IV) complexes were linked to terminal NH<sub>2</sub> moieties of PAMAM dendrime...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-05-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/15/5/1515 |
| _version_ | 1827740345580912640 |
|---|---|
| author | Yvonne Lerchbammer-Kreith Michaela Hejl Petra Vician Michael A. Jakupec Walter Berger Mathea S. Galanski Bernhard K. Keppler |
| author_facet | Yvonne Lerchbammer-Kreith Michaela Hejl Petra Vician Michael A. Jakupec Walter Berger Mathea S. Galanski Bernhard K. Keppler |
| author_sort | Yvonne Lerchbammer-Kreith |
| collection | DOAJ |
| description | Based on their drug delivery properties and activity against tumors, we combined PAMAM dendrimers with various platinum(IV) complexes in order to provide an improved approach of anticancer treatment. Platinum(IV) complexes were linked to terminal NH<sub>2</sub> moieties of PAMAM dendrimers of generation 2 (G2) and 4 (G4) via amide bonds. Conjugates were characterized by <sup>1</sup>H and <sup>195</sup>Pt NMR spectroscopy, ICP-MS and in representative cases by pseudo-2D diffusion-ordered NMR spectroscopy. Additionally, the reduction behavior of conjugates in comparison to corresponding platinum(IV) complexes was investigated, showing a faster reduction of conjugates. Cytotoxicity was evaluated via the MTT assay in human cell lines (A549, CH1/PA-1, SW480), revealing IC<sub>50</sub> values in the low micromolar to high picomolar range. The synergistic combination of PAMAM dendrimers and platinum(IV) complexes resulted in up to 200 times increased cytotoxic activity of conjugates in consideration of the loaded platinum(IV) units compared to their platinum(IV) counterparts. The lowest IC<sub>50</sub> value of 780 ± 260 pM in the CH1/PA-1 cancer cell line was detected for an oxaliplatin-based G4 PAMAM dendrimer conjugate. Finally, in vivo experiments of a cisplatin-based G4 PAMAM dendrimer conjugate were performed based on the best toxicological profile. A maximum tumor growth inhibition effect of 65.6% compared to 47.6% for cisplatin was observed as well as a trend of prolonged animal survival. |
| first_indexed | 2024-03-11T03:24:38Z |
| format | Article |
| id | doaj.art-a76602e5e3d84c4bb7a76ae7b269b879 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-11T03:24:38Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-a76602e5e3d84c4bb7a76ae7b269b8792023-11-18T02:52:43ZengMDPI AGPharmaceutics1999-49232023-05-01155151510.3390/pharmaceutics15051515Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment?Yvonne Lerchbammer-Kreith0Michaela Hejl1Petra Vician2Michael A. Jakupec3Walter Berger4Mathea S. Galanski5Bernhard K. Keppler6Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaCenter for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaInstitute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, AustriaBased on their drug delivery properties and activity against tumors, we combined PAMAM dendrimers with various platinum(IV) complexes in order to provide an improved approach of anticancer treatment. Platinum(IV) complexes were linked to terminal NH<sub>2</sub> moieties of PAMAM dendrimers of generation 2 (G2) and 4 (G4) via amide bonds. Conjugates were characterized by <sup>1</sup>H and <sup>195</sup>Pt NMR spectroscopy, ICP-MS and in representative cases by pseudo-2D diffusion-ordered NMR spectroscopy. Additionally, the reduction behavior of conjugates in comparison to corresponding platinum(IV) complexes was investigated, showing a faster reduction of conjugates. Cytotoxicity was evaluated via the MTT assay in human cell lines (A549, CH1/PA-1, SW480), revealing IC<sub>50</sub> values in the low micromolar to high picomolar range. The synergistic combination of PAMAM dendrimers and platinum(IV) complexes resulted in up to 200 times increased cytotoxic activity of conjugates in consideration of the loaded platinum(IV) units compared to their platinum(IV) counterparts. The lowest IC<sub>50</sub> value of 780 ± 260 pM in the CH1/PA-1 cancer cell line was detected for an oxaliplatin-based G4 PAMAM dendrimer conjugate. Finally, in vivo experiments of a cisplatin-based G4 PAMAM dendrimer conjugate were performed based on the best toxicological profile. A maximum tumor growth inhibition effect of 65.6% compared to 47.6% for cisplatin was observed as well as a trend of prolonged animal survival.https://www.mdpi.com/1999-4923/15/5/1515platinum(IV) complexesPAMAM dendrimersanticancerdrug delivery |
| spellingShingle | Yvonne Lerchbammer-Kreith Michaela Hejl Petra Vician Michael A. Jakupec Walter Berger Mathea S. Galanski Bernhard K. Keppler Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment? Pharmaceutics platinum(IV) complexes PAMAM dendrimers anticancer drug delivery |
| title | Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment? |
| title_full | Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment? |
| title_fullStr | Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment? |
| title_full_unstemmed | Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment? |
| title_short | Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment? |
| title_sort | combination of drug delivery properties of pamam dendrimers and cytotoxicity of platinum iv complexes a more selective anticancer treatment |
| topic | platinum(IV) complexes PAMAM dendrimers anticancer drug delivery |
| url | https://www.mdpi.com/1999-4923/15/5/1515 |
| work_keys_str_mv | AT yvonnelerchbammerkreith combinationofdrugdeliverypropertiesofpamamdendrimersandcytotoxicityofplatinumivcomplexesamoreselectiveanticancertreatment AT michaelahejl combinationofdrugdeliverypropertiesofpamamdendrimersandcytotoxicityofplatinumivcomplexesamoreselectiveanticancertreatment AT petravician combinationofdrugdeliverypropertiesofpamamdendrimersandcytotoxicityofplatinumivcomplexesamoreselectiveanticancertreatment AT michaelajakupec combinationofdrugdeliverypropertiesofpamamdendrimersandcytotoxicityofplatinumivcomplexesamoreselectiveanticancertreatment AT walterberger combinationofdrugdeliverypropertiesofpamamdendrimersandcytotoxicityofplatinumivcomplexesamoreselectiveanticancertreatment AT matheasgalanski combinationofdrugdeliverypropertiesofpamamdendrimersandcytotoxicityofplatinumivcomplexesamoreselectiveanticancertreatment AT bernhardkkeppler combinationofdrugdeliverypropertiesofpamamdendrimersandcytotoxicityofplatinumivcomplexesamoreselectiveanticancertreatment |