Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation
The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/13/10/1609 |
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| author | Víctor González-Ruiz Ángel Cores Olmo Martín-Cámara Karen Orellana Víctor Cervera-Carrascón Patrycja Michalska Ana I. Olives Rafael León M. Antonia Martín J. Carlos Menéndez |
| author_facet | Víctor González-Ruiz Ángel Cores Olmo Martín-Cámara Karen Orellana Víctor Cervera-Carrascón Patrycja Michalska Ana I. Olives Rafael León M. Antonia Martín J. Carlos Menéndez |
| author_sort | Víctor González-Ruiz |
| collection | DOAJ |
| description | The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR). The variations in the <sup>1</sup>H-NMR and <sup>13</sup>C-NMR chemical shifts allowed to establish the inclusion modes of the compounds into the cyclodextrin cavities, which were supported by docking and molecular dynamics studies. The efficiency of the complexation was quantified by UV-Vis spectrophotometry and spectrofluorimetry, which showed that the protonation equilibria of camptothecin and luotonin A were drastically hampered upon formation of the inclusion complexes. The stabilization of camptothecin towards hydrolysis inside the cyclodextrin cavity was verified by the quantitation of the active lactone form by reverse phase liquid chromatography fluorimetric detection, both in basic conditions and in the presence of serum albumin. The antitumor activity of luotonin A and camptothecin complexes were studied in several cancer cell lines (breast, lung, hepatic carcinoma, ovarian carcinoma and human neuroblastoma) and an enhanced activity was found compared to the free alkaloids, particularly in the case of hydroxypropyl-β-cyclodextrin derivatives. This result shows that the cyclodextrin inclusion strategy has much potential towards reaching the goal of employing luotonin A or its analogues as stable analogues of camptothecin. |
| first_indexed | 2024-03-10T06:16:14Z |
| format | Article |
| id | doaj.art-6087facd475e40e3a8511f0fb3b94f4e |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T06:16:14Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-6087facd475e40e3a8511f0fb3b94f4e2023-11-22T19:38:27ZengMDPI AGPharmaceutics1999-49232021-10-011310160910.3390/pharmaceutics13101609Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin ComplexationVíctor González-Ruiz0Ángel Cores1Olmo Martín-Cámara2Karen Orellana3Víctor Cervera-Carrascón4Patrycja Michalska5Ana I. Olives6Rafael León7M. Antonia Martín8J. Carlos Menéndez9Swiss Centre for Applied Human Toxicology, School of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, 1205 Geneva, SwitzerlandUnidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, SpainUnidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, SpainFacultad de Química y Farmacia, Universidad Nacional Autónoma de Honduras (UNAH), 11101 Tegucigalpa, HondurasUnidad de Química Analítica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, SpainInstituto Teófilo Hernando y Departamento de Farmacologia y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, 28049 Madrid, SpainUnidad de Química Analítica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, SpainInstituto de Química Médica, Consejo Superior de Investigaciones Científicas, 28006 Madrid, SpainUnidad de Química Analítica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, SpainUnidad de Química Orgánica y Farmacéutica, Departamento de Química en Ciencias Farmacéuticas, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, SpainThe use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR). The variations in the <sup>1</sup>H-NMR and <sup>13</sup>C-NMR chemical shifts allowed to establish the inclusion modes of the compounds into the cyclodextrin cavities, which were supported by docking and molecular dynamics studies. The efficiency of the complexation was quantified by UV-Vis spectrophotometry and spectrofluorimetry, which showed that the protonation equilibria of camptothecin and luotonin A were drastically hampered upon formation of the inclusion complexes. The stabilization of camptothecin towards hydrolysis inside the cyclodextrin cavity was verified by the quantitation of the active lactone form by reverse phase liquid chromatography fluorimetric detection, both in basic conditions and in the presence of serum albumin. The antitumor activity of luotonin A and camptothecin complexes were studied in several cancer cell lines (breast, lung, hepatic carcinoma, ovarian carcinoma and human neuroblastoma) and an enhanced activity was found compared to the free alkaloids, particularly in the case of hydroxypropyl-β-cyclodextrin derivatives. This result shows that the cyclodextrin inclusion strategy has much potential towards reaching the goal of employing luotonin A or its analogues as stable analogues of camptothecin.https://www.mdpi.com/1999-4923/13/10/1609molecular recognitioncavitandssupramolecular complexesanticancer agentsdrug stabilization |
| spellingShingle | Víctor González-Ruiz Ángel Cores Olmo Martín-Cámara Karen Orellana Víctor Cervera-Carrascón Patrycja Michalska Ana I. Olives Rafael León M. Antonia Martín J. Carlos Menéndez Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation Pharmaceutics molecular recognition cavitands supramolecular complexes anticancer agents drug stabilization |
| title | Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation |
| title_full | Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation |
| title_fullStr | Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation |
| title_full_unstemmed | Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation |
| title_short | Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation |
| title_sort | enhanced stability and bioactivity of natural anticancer topoisomerase i inhibitors through cyclodextrin complexation |
| topic | molecular recognition cavitands supramolecular complexes anticancer agents drug stabilization |
| url | https://www.mdpi.com/1999-4923/13/10/1609 |
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