Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis

PLoS Pathogens

José Maceira¹  Harry P. de Koning¹  Manuel Muñóz-Torres¹  Stefan Magez²  Miguel Soriano³  José Hernández-Quero⁴  José L. Arias⁴  Juan D. Unciti-Broceta⁵  Matilde Ortiz-González⁵  José A. Garcia-Salcedo⁵ 

[1] Centro Pfizer-Universidad de Granada-Junta de Andalucía de Genómica e Investigación Oncológica (GENYO), PTS Granada, Granada, Spain;Departamento de Agronomía, Universidad de Almería, Almería, Spain;Departamento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Granada, Granada, Spain;Instituto de Parasitología y Biomedicina “López-Neyra” (IPBLN-CSIC), PTS Granada, Armilla, Spain;Unidad de Enfermedades Infecciosas y Microbiología, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain

关键词: Trypanosoma;    Nanoparticles;    Parasitic diseases;    Mouse models;    Blood;    Trypanosoma brucei gambiense;    Polymerase chain reaction;    Drug delivery;   

DOI  :  10.1371/journal.ppat.1004942

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY