Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo
Artemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-12-01
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| Series: | Polymers |
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| Online Access: | https://www.mdpi.com/2073-4360/14/24/5503 |
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| author | Alessandra Teixeira Vidal-Diniz Homero Nogueira Guimarães Giani Martins Garcia Érika Martins Braga Sylvain Richard Andrea Grabe-Guimarães Vanessa Carla Furtado Mosqueira |
| author_facet | Alessandra Teixeira Vidal-Diniz Homero Nogueira Guimarães Giani Martins Garcia Érika Martins Braga Sylvain Richard Andrea Grabe-Guimarães Vanessa Carla Furtado Mosqueira |
| author_sort | Alessandra Teixeira Vidal-Diniz |
| collection | DOAJ |
| description | Artemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardiotoxicity. To achieve this, we prepared polymeric nanocapsules (NCs) from different biodegradable polyesters, namely poly(<i>D,L</i>-lactide) (PLA), poly-ε-caprolactone (PCL), and surface-modified NCs, using a monomethoxi-polyethylene glycol-<i>block</i>-poly(<i>D,L</i>-lactide) (PEG<sub>5kDa</sub>-PLA<sub>45kDa</sub>) polymer. Using this approach, we were able to encapsulate high yields of ATM (>85%, 0–4 mg/mL) within the oily core of the NCs. The PCL-NCs exhibited the highest percentage of ATM loading as well as a slow release rate. Atomic force microscopy showed nanometric and spherical particles with a narrow size dispersion. We used the PCL NCs loaded with ATM for biological evaluation following IV administration. As with free-ATM, the ATM-PCL-NCs formulation exhibited potent antimalarial efficacy using either the “Four-day test” protocol (ATM total at the end of the 4 daily doses: 40 and 80 mg/kg) in Swiss mice infected with <i>P. berghei</i> or a single low dose (20 mg/kg) of ATM in mice with higher parasitemia (15%). In healthy rats, IV administration of single doses of free-ATM (40 or 80 mg/kg) prolonged cardiac QT and QTc intervals and induced both bradycardia and hypotension. Repeated IV administration of free-ATM (four IV doses at 20 mg/kg every 12 h for 48 h) also prolonged the QT and QTc intervals but, paradoxically, induced tachycardia and hypertension. Remarkably, the incorporation of ATM in ATM-PCL-NCs reduced all adverse effects. In conclusion, the encapsulation of ATM in biodegradable polyester NCs reduces its cardiovascular toxicity without affecting its antimalarial efficacy. |
| first_indexed | 2024-03-09T15:55:29Z |
| format | Article |
| id | doaj.art-714f29a04b8848069e5358ab8b765937 |
| institution | Directory Open Access Journal |
| issn | 2073-4360 |
| language | English |
| last_indexed | 2024-03-09T15:55:29Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Polymers |
| spelling | doaj.art-714f29a04b8848069e5358ab8b7659372023-11-24T17:33:14ZengMDPI AGPolymers2073-43602022-12-011424550310.3390/polym14245503Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In VivoAlessandra Teixeira Vidal-Diniz0Homero Nogueira Guimarães1Giani Martins Garcia2Érika Martins Braga3Sylvain Richard4Andrea Grabe-Guimarães5Vanessa Carla Furtado Mosqueira6School of Pharmacy, Universidade Federal de Ouro Preto (UFOP), Campus Universitário Morro do Cruzeiro, Ouro Preto 35400-000, MG, BrazilDepartment of Electrical Engineering, Federal University of Minas Gerais, Belo Horizonte 31270-901, MG, BrazilSchool of Pharmacy, Universidade Federal de Ouro Preto (UFOP), Campus Universitário Morro do Cruzeiro, Ouro Preto 35400-000, MG, BrazilDepartment of Parasitology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte 31270-901, MG, BrazilCNRS, INSERM, Université de Montpellier, 34295 Montpellier, FranceSchool of Pharmacy, Universidade Federal de Ouro Preto (UFOP), Campus Universitário Morro do Cruzeiro, Ouro Preto 35400-000, MG, BrazilSchool of Pharmacy, Universidade Federal de Ouro Preto (UFOP), Campus Universitário Morro do Cruzeiro, Ouro Preto 35400-000, MG, BrazilArtemether (ATM) is an effective antimalarial drug that also has a short half-life in the blood. Furthermore, ATM is also cardiotoxic and is associated with pro-arrhythmogenic risks. We aimed to develop a delivery system enabling the prolonged release of ATM into the blood coupled with reduced cardiotoxicity. To achieve this, we prepared polymeric nanocapsules (NCs) from different biodegradable polyesters, namely poly(<i>D,L</i>-lactide) (PLA), poly-ε-caprolactone (PCL), and surface-modified NCs, using a monomethoxi-polyethylene glycol-<i>block</i>-poly(<i>D,L</i>-lactide) (PEG<sub>5kDa</sub>-PLA<sub>45kDa</sub>) polymer. Using this approach, we were able to encapsulate high yields of ATM (>85%, 0–4 mg/mL) within the oily core of the NCs. The PCL-NCs exhibited the highest percentage of ATM loading as well as a slow release rate. Atomic force microscopy showed nanometric and spherical particles with a narrow size dispersion. We used the PCL NCs loaded with ATM for biological evaluation following IV administration. As with free-ATM, the ATM-PCL-NCs formulation exhibited potent antimalarial efficacy using either the “Four-day test” protocol (ATM total at the end of the 4 daily doses: 40 and 80 mg/kg) in Swiss mice infected with <i>P. berghei</i> or a single low dose (20 mg/kg) of ATM in mice with higher parasitemia (15%). In healthy rats, IV administration of single doses of free-ATM (40 or 80 mg/kg) prolonged cardiac QT and QTc intervals and induced both bradycardia and hypotension. Repeated IV administration of free-ATM (four IV doses at 20 mg/kg every 12 h for 48 h) also prolonged the QT and QTc intervals but, paradoxically, induced tachycardia and hypertension. Remarkably, the incorporation of ATM in ATM-PCL-NCs reduced all adverse effects. In conclusion, the encapsulation of ATM in biodegradable polyester NCs reduces its cardiovascular toxicity without affecting its antimalarial efficacy.https://www.mdpi.com/2073-4360/14/24/5503nanocapsulesQT intervalcardiotoxicityartemethermalariaself-assembled polymers |
| spellingShingle | Alessandra Teixeira Vidal-Diniz Homero Nogueira Guimarães Giani Martins Garcia Érika Martins Braga Sylvain Richard Andrea Grabe-Guimarães Vanessa Carla Furtado Mosqueira Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo Polymers nanocapsules QT interval cardiotoxicity artemether malaria self-assembled polymers |
| title | Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo |
| title_full | Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo |
| title_fullStr | Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo |
| title_full_unstemmed | Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo |
| title_short | Polyester Nanocapsules for Intravenous Delivery of Artemether: Formulation Development, Antimalarial Efficacy, and Cardioprotective Effects In Vivo |
| title_sort | polyester nanocapsules for intravenous delivery of artemether formulation development antimalarial efficacy and cardioprotective effects in vivo |
| topic | nanocapsules QT interval cardiotoxicity artemether malaria self-assembled polymers |
| url | https://www.mdpi.com/2073-4360/14/24/5503 |
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