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Open Access Original paper

Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors

Patricia Urbán123, Joan Estelrich24, Alberto Adeva5, Alfred Cortés367 and Xavier Fernàndez-Busquets123*

Author Affiliations

1 Nanobioengineering Group, Institute for Bioengineering of Catalonia, Baldiri Reixac 10-12, Barcelona, E08028, Spain

2 Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona (UB), Martí i Franquès 1, Barcelona, E08028, Spain

3 Barcelona Centre for International Health Research (CRESIB), Hospital Clínic-Universitat de Barcelona, Rosselló 132, Barcelona, E08036, Spain

4 Departament de Fisicoquímica, Facultat de Farmàcia, University of Barcelona, Av. Joan XXIII, s/n, Barcelona, E08028, Spain

5 Scientific and Technological Centres, University of Barcelona, Baldiri Reixac 10-12, Barcelona, E08028, Spain

6 Institute for Research in Biomedicine, Barcelona Science Park, Baldiri Reixac 10-12, Barcelona, E08028, Spain

7 Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, Barcelona, E08018, Spain

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Nanoscale Research Letters 2011, 6:620  doi:10.1186/1556-276X-6-620

Published: 7 December 2011

Abstract

Paul Ehrlich's dream of a 'magic bullet' that would specifically destroy invading microbes is now a major aspect of clinical medicine. However, a century later, the implementation of this medical holy grail continues being a challenge in three main fronts: identifying the right molecular or cellular targets for a particular disease, having a drug that is effective against it, and finding a strategy for the efficient delivery of sufficient amounts of the drug in an active state exclusively to the selected targets. In a previous work, we engineered an immunoliposomal nanovector for the targeted delivery of its contents exclusively to Plasmodium falciparum-infected red blood cells [pRBCs]. In preliminary assays, the antimalarial drug chloroquine showed improved efficacy when delivered inside immunoliposomes targeted with the pRBC-specific monoclonal antibody BM1234. Because difficulties in determining the exact concentration of the drug due to its low amounts prevented an accurate estimation of the nanovector performance, here, we have developed an HPLC-based method for the precise determination of the concentrations in the liposomal preparations of chloroquine and of a second antimalarial drug, fosmidomycin. The results obtained indicate that immunoliposome encapsulation of chloroquine and fosmidomycin improves by tenfold the efficacy of antimalarial drugs. The targeting antibody used binds preferentially to pRBCs containing late maturation stages of the parasite. In accordance with this observation, the best performing immunoliposomes are those added to Plasmodium cultures having a larger number of late form-containing pRBCs. An average of five antibody molecules per liposome significantly improves in cell cultures the performance of immunoliposomes over non-functionalized liposomes as drug delivery vessels. Increasing the number of antibodies on the liposome surface correspondingly increases performance, with a reduction of 50% parasitemia achieved with immunoliposomes encapsulating 4 nM chloroquine and bearing an estimated 250 BM1234 units. The nanovector prototype described here can be a valuable platform amenable to modification and improvement with the objective of designing a nanostructure adequate to enter the preclinical pipeline as a new antimalarial therapy.

Keywords:
antimalarial chemotherapy; chloroquine; fosmidomycin; half-antibodies; immunoliposomes; malaria; nanomedicine; targeted drug delivery