期刊
JOURNAL OF CONTROLLED RELEASE
卷 241, 期 -, 页码 57-67出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2016.09.006
关键词
Combination therapy; Immunoliposomes; Malaria; Nanomedicine; Rosetting; Targeted drug delivery
资金
- Ministerio de Economia y Competitividad (MINECO), Spain [BIO2011-25039, BIO2014-52872-R]
- Generalitat de Catalunya, Spain [2014-SGR-938]
- Subprograma de Formacion de Personal Investigador, MINECO, Spain
- FEDER funds
Parasite proteins exported to the surface of Plasmodium falciparum-parasitized red blood cells (pRBCs) have a major role in severe malaria clinical manifestation, where pRBC cytoadhesion and rosetting processes have been strongly linked with microvascular sequestration while avoiding both spleen filtration and immune surveillance. The parasite-derived and pRBC surface-exposed PfEMP1 protein has been identified as one of the responsible elements for rosetting and, therefore, considered as a promising vaccine candidate for the generation of rosette-disrupting antibodies against severe malaria. However, the potential role of anti-rosetting antibodies as targeting molecules for the functionalization of antimalarial drug-loaded nanovectors has never been studied. Our manuscript presents a proof-of-concept study where the activity of an immunoliposomal vehicle with a dual performance capable of specifically recognizing and disrupting rosettes while simultaneously eliminating those pRBCs forming them has been assayed in vitro. A polyclonal antibody against the NTS-DBL1 alpha N-terminal domain of a rosetting PfEMP1 variant has been selected as targeting molecule and lumefantrine as the antimalarial payload. After 30 min incubation with 2 mu M encapsulated drug, a 70% growth inhibition for all parasitic forms in culture (IC50: 414 nM) and a reduction in ca. 60% of those pRBCs with a rosetting phenotype (IC50: 747 nM) were achieved. This immunoliposomal approach represents an innovative combination therapy for the improvement of severe malaria therapeutics having a broader spectrum of activity than either anti-rosetting antibodies or free drugs on their own. (C) 2016 Elsevier B.V. All rights reserved.
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