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PEGylated Dendritic Polyglycerol Conjugate Delivers Doxorubicin to the Parasitophorous Vacuole in Leishmania infantum Infections.
Gutierrez-Corbo, Camino; Dominguez-Asenjo, Barbara; Vossen, Laura I; Pérez-Pertejo, Yolanda; Muñoz-Fenández, Maria A; Balaña-Fouce, Rafael; Calderón, Marcelo; Reguera, Rosa M.
Affiliation
  • Gutierrez-Corbo C; Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, 24071, León, Spain.
  • Dominguez-Asenjo B; Laboratorio de InmunoBiologia Molecular, Hospital General Universitario Gregorio Marañon, Spanish HIV HGM BioBank, IiSGM and CIBER-BBN, 28007, Madrid, Spain.
  • Vossen LI; Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, 24071, León, Spain.
  • Pérez-Pertejo Y; Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany.
  • Muñoz-Fenández MA; Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, 24071, León, Spain.
  • Balaña-Fouce R; Laboratorio de InmunoBiologia Molecular, Hospital General Universitario Gregorio Marañon, Spanish HIV HGM BioBank, IiSGM and CIBER-BBN, 28007, Madrid, Spain.
  • Calderón M; Departamento de Ciencias Biomédicas, Facultad de Veterinaria, Universidad de León, 24071, León, Spain.
  • Reguera RM; Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195, Berlin, Germany.
Macromol Biosci ; 17(10)2017 10.
Article in En | MEDLINE | ID: mdl-28683183
ABSTRACT
Most drugs against visceral leishmaniasis must be administered parenterally. A controlled drug release at the target site can improve the efficacy and toxicity of antileishmanial drugs in clinical use. Amastigotes live and grow inside the parasitophorous vacuole of host resident macrophages. Therefore, antileishmanial drugs should accumulate in this compartment to kill the parasite and do not produce toxicity to the cell host. PEGylated dendritic polyglycerol conjugates (PG-PEG) can ensure a controlled drug release and the immune activation efficiency of the host. A dendritic PG conjugate with doxorubicin (DOX) attached through a pH-cleavable hydrazone linker (PG-DOX(pH)-PEG), is tested on murine macrophage cell lines and on ex vivo infected BALB/c splenocytes. As a control, a dendritic PG conjugate attached via a non-cleavable linker (PG-DOX(non)-PEG) is used. DOX fluorescence is useful to monitor the fate of the drug inside the infected cells by flow cytometry and confocal microscopy. The results show that PG-DOX(pH)-PEG slowly releases DOX inside the targeted macrophages, protecting the host of toxic drug concentrations. In addition, unlike free DOX, PG-DOX(pH)-PEG is actively internalized through the acidic endocytic pathway and colocalized surrounding the amastigotes. These results prove that PG-DOX(pH)-PEG is a promising candidate for releasing antileishmanial drugs in a controlled manner.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polyethylene Glycols / Polymers / Doxorubicin / Leishmania infantum / Delayed-Action Preparations / Glycerol / Leishmaniasis, Visceral / Macrophages Limits: Animals / Female / Humans Language: En Journal: Macromol Biosci Journal subject: BIOQUIMICA Year: 2017 Document type: Article Affiliation country: Spain

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Polyethylene Glycols / Polymers / Doxorubicin / Leishmania infantum / Delayed-Action Preparations / Glycerol / Leishmaniasis, Visceral / Macrophages Limits: Animals / Female / Humans Language: En Journal: Macromol Biosci Journal subject: BIOQUIMICA Year: 2017 Document type: Article Affiliation country: Spain