Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.
African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The i...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-06-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1004942 |
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| author | Juan D Unciti-Broceta José L Arias José Maceira Miguel Soriano Matilde Ortiz-González José Hernández-Quero Manuel Muñóz-Torres Harry P de Koning Stefan Magez José A Garcia-Salcedo |
| author_facet | Juan D Unciti-Broceta José L Arias José Maceira Miguel Soriano Matilde Ortiz-González José Hernández-Quero Manuel Muñóz-Torres Harry P de Koning Stefan Magez José A Garcia-Salcedo |
| author_sort | Juan D Unciti-Broceta |
| collection | DOAJ |
| description | African trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs. |
| format | Article |
| id | doaj-art-62cf768c8f2b4d82a0cdb7aa2efb57a9 |
| institution | DOAJ |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-62cf768c8f2b4d82a0cdb7aa2efb57a92025-08-20T03:10:04ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-06-01116e100494210.1371/journal.ppat.1004942Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis.Juan D Unciti-BrocetaJosé L AriasJosé MaceiraMiguel SorianoMatilde Ortiz-GonzálezJosé Hernández-QueroManuel Muñóz-TorresHarry P de KoningStefan MagezJosé A Garcia-SalcedoAfrican trypanosomiasis is a deadly neglected disease caused by the extracellular parasite Trypanosoma brucei. Current therapies are characterized by high drug toxicity and increasing drug resistance mainly associated with loss-of-function mutations in the transporters involved in drug import. The introduction of new antiparasitic drugs into therapeutic use is a slow and expensive process. In contrast, specific targeting of existing drugs could represent a more rapid and cost-effective approach for neglected disease treatment, impacting through reduced systemic toxicity and circumventing resistance acquired through impaired compound uptake. We have generated nanoparticles of chitosan loaded with the trypanocidal drug pentamidine and coated by a single domain nanobody that specifically targets the surface of African trypanosomes. Once loaded into this nanocarrier, pentamidine enters trypanosomes through endocytosis instead of via classical cell surface transporters. The curative dose of pentamidine-loaded nanobody-chitosan nanoparticles was 100-fold lower than pentamidine alone in a murine model of acute African trypanosomiasis. Crucially, this new formulation displayed undiminished in vitro and in vivo activity against a trypanosome cell line resistant to pentamidine as a result of mutations in the surface transporter aquaglyceroporin 2. We conclude that this new drug delivery system increases drug efficacy and has the ability to overcome resistance to some anti-protozoal drugs.https://doi.org/10.1371/journal.ppat.1004942 |
| spellingShingle | Juan D Unciti-Broceta José L Arias José Maceira Miguel Soriano Matilde Ortiz-González José Hernández-Quero Manuel Muñóz-Torres Harry P de Koning Stefan Magez José A Garcia-Salcedo Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. PLoS Pathogens |
| title | Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. |
| title_full | Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. |
| title_fullStr | Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. |
| title_full_unstemmed | Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. |
| title_short | Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis. |
| title_sort | specific cell targeting therapy bypasses drug resistance mechanisms in african trypanosomiasis |
| url | https://doi.org/10.1371/journal.ppat.1004942 |
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