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by Keyword: antimalarial


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Quiliano, Miguel, Pabón, Adriana, Moles, Ernest, Bonilla-Ramirez, Leonardo, Fabing, Isabelle, Fong, Kim Y., Nieto-Aco, Diego A., Wright, David W., Pizarro, Juan C., Vettorazzi, Ariane, López de Cerain, Adela, Deharo, Eric, Fernàndez-Busquets, Xavier, Garavito, Giovanny, Aldana, Ignacio, Galiano, Silvia, (2018). Structure-activity relationship of new antimalarial 1-aryl-3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery European Journal of Medicinal Chemistry 152, 489-514

Design, synthesis, structure-activity relationship, cytotoxicity studies, in silico drug-likeness, genotoxicity screening, and in vivo studies of new 1-aryl-3-substituted propanol derivatives led to the identification of nine compounds with promising in vitro (55, 56, 61, 64, 66, and 70–73) and in vivo (66 and 72) antimalarial profiles against Plasmodium falciparum and Plasmodium berghei. Compounds 55, 56, 61, 64, 66 and 70–73 exhibited potent antiplasmodial activity against chloroquine-resistant strain FCR-3 (IC50s < 0.28 μM), and compounds 55, 56, 64, 70, 71, and 72 showed potent biological activity in chloroquine-sensitive and multidrug-resistant strains (IC50s < 0.7 μM for 3D7, D6, FCR-3 and C235). All of these compounds share appropriate drug-likeness profiles and adequate selectivity indexes (77 < SI < 184) as well as lack genotoxicity. In vivo efficacy tests in a mouse model showed compounds 66 and 72 to be promising candidates as they exhibited significant parasitemia reductions of 96.4% and 80.4%, respectively. Additional studies such as liver stage and sporogony inhibition, target exploration of heat shock protein 90 of P. falciparum, targeted delivery by immunoliposomes, and enantiomer characterization were performed and strongly reinforce the hypothesis of 1-aryl-3-substituted propanol derivatives as promising antimalarial compounds.

Keywords: Antiplasmodial, Antimalarial, Arylamino alcohol, Multi-stage activity, Hsp90, Enantiomer separation


Martí Coma-Cros, E., Biosca, A., Marques, J., Carol, L., Urbán, P., Berenguer, D., Riera, M. C., Delves, M., Sinden, R. E., Valle-Delgado, J. J., Spanos, L., Siden-Kiamos, I., Pérez, P., Paaijmans, K., Rottmann, M., Manfredi, A., Ferruti, P., Ranucci, E., Fernàndez-Busquets, X., (2018). Polyamidoamine nanoparticles for the oral administration of antimalarial drugs Pharmaceutics 10, (4), 225

Current strategies for the mass administration of antimalarial drugs demand oral formulations to target the asexual Plasmodium stages in the peripheral bloodstream, whereas recommendations for future interventions stress the importance of also targeting the transmission stages of the parasite as it passes between humans and mosquitoes. Orally administered polyamidoamine (PAA) nanoparticles conjugated to chloroquine reached the blood circulation and cured Plasmodium yoelii-infected mice, slightly improving the activity of the free drug and inducing in the animals immunity against malaria. Liquid chromatography with tandem mass spectrometry analysis of affinity chromatography-purified PAA ligands suggested a high adhesiveness of PAAs to Plasmodium falciparum proteins, which might be the mechanism responsible for the preferential binding of PAAs to Plasmodium-infected erythrocytes vs. non-infected red blood cells. The weak antimalarial activity of some PAAs was found to operate through inhibition of parasite invasion, whereas the observed polymer intake by macrophages indicated a potential of PAAs for the treatment of certain coinfections such as Plasmodium and Leishmania. When fluorescein-labeled PAAs were fed to females of the malaria mosquito vectors Anopheles atroparvus and Anopheles gambiae, persistent fluorescence was observed in the midgut and in other insect’s tissues. These results present PAAs as a versatile platform for the encapsulation of orally administered antimalarial drugs and for direct administration of antimalarials to mosquitoes, targeting mosquito stages of Plasmodium.

Keywords: Anopheles, Antimalarial drugs, Malaria, Mosquitoes, Nanomedicine, Nanotechnology, Plasmodium, Polyamidoamines, Polymers, Targeted drug delivery


Aláez-Versón, C. R., Lantero, E., Fernàndez-Busquets, X., (2017). Heparin: New life for an old drug Nanomedicine 12, (14), 1727-1744

Heparin is one of the oldest drugs, which nevertheless remains in widespread clinical use as an inhibitor of blood coagulation. The history of its identification a century ago unfolded amid one of the most fascinating scientific controversies turning around the distribution of credit for its discovery. The composition, purification and structure-function relationship of this naturally occurring glycosaminoglycan regarding its classical role as anticoagulant will be dealt with before proceeding to discuss its therapeutic potential in, among other, inflammatory and infectious disease, cancer treatment, cystic fibrosis and Alzheimer's disease. The first bibliographic reference hit using the words 'nanomedicine' and 'heparin' is as recent as 2008. Since then, nanomedical applications of heparin have experienced an exponential growth that will be discussed in detail, with particular emphasis on its antimalarial activity. Some of the most intriguing potential applications of heparin nanomedicines will be exposed, such as those contemplating the delivery of drugs to the mosquito stages of malaria parasites.

Keywords: Anopheles, Antimalarial drugs, Heparin, Malaria, Mosquitoes, Nanomedicine, Nanotechnology, Plasmodium, Targeted drug delivery


Fernàndez-Busquets, X., (2016). Novel strategies for Plasmodium-targeted drug delivery Expert Opinion on Drug Delivery , 13, (7), 919-922

Fernàndez-Busquets, X., (2014). Toy kit against malaria: Magic bullets, LEGO, Trojan horses and Russian dolls Therapeutic Delivery , 5, (10), 1049-1052

Movellan, J., Urbán, P., Moles, E., de la Fuente, J. M., Sierra, T., Serrano, J. L., Fernàndez-Busquets, X., (2014). Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs Biomaterials 35, (27), 7940-7950

It can be foreseen that in a future scenario of malaria eradication, a varied armamentarium will be required, including strategies for the targeted administration of antimalarial compounds. The development of nanovectors capable of encapsulating drugs and of delivering them to Plasmodium-infected cells with high specificity and efficacy and at an affordable cost is of particular interest. With this objective, dendritic derivatives based on 2,2-bis(hydroxymethyl)propionic acid (bis-MPA) and Pluronic® polymers have been herein explored. Four different dendritic derivatives have been tested for their capacity to encapsulate the antimalarial drugs chloroquine (CQ) and primaquine (PQ), their specific targeting to Plasmodium-infected red blood cells (pRBCs), and their antimalarial activity in vitro against the human pathogen Plasmodium falciparum and in vivo against the rodent malaria species Plasmodium yoelii. The results obtained have allowed the identification of two dendritic derivatives exhibiting specific targeting to pRBCs vs. non-infected RBCs, which reduce the in vitro IC50 of CQ and PQ by ca. 3- and 4-fold down to 4.0 nm and 1.1 μm, respectively. This work on the application of dendritic derivatives to antimalarial targeted drug delivery opens the way for the use of this new type of chemicals in future malaria eradication programs.

Keywords: Antimalarial targeted drug delivery, Dendrimers, Malaria, Nanomedicine, Plasmodium, Polymeric nanoparticles


Marques, J., Moles, E., Urbán, P., Prohens, R., Busquets, M. A., Sevrin, C., Grandfils, C., Fernàndez-Busquets, X., (2014). Application of heparin as a dual agent with antimalarial and liposome targeting activities toward Plasmodium-infected red blood cells Nanomedicine: Nanotechnology, Biology, and Medicine 10, (8), 1719-1728

Heparin had been demonstrated to have antimalarial activity and specific binding affinity for Plasmodium-infected red blood cells (pRBCs) vs. non-infected erythrocytes. Here we have explored if both properties could be joined into a drug delivery strategy where heparin would have a dual role as antimalarial and as a targeting element of drug-loaded nanoparticles. Confocal fluorescence and transmission electron microscopy data show that after 30. min of being added to living pRBCs fluorescein-labeled heparin colocalizes with the intracellular parasites. Heparin electrostatically adsorbed onto positively charged liposomes containing the cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane and loaded with the antimalarial drug primaquine was capable of increasing three-fold the activity of encapsulated drug in Plasmodium falciparum cultures. At concentrations below those inducing anticoagulation of mouse blood in vivo, parasiticidal activity was found to be the additive result of the separate activities of free heparin as antimalarial and of liposome-bound heparin as targeting element for encapsulated primaquine. From the Clinical Editor: Malaria remains an enormous global public health concern. In this study, a novel functionalized heparin formulation used as drug delivery agent for primaquine was demonstrated to result in threefold increased drug activity in cell cultures, and in a murine model it was able to provide these benefits in concentrations below what would be required for anticoagulation. Further studies are needed determine if this approach is applicable in the human disease as well.

Keywords: Heparin, Liposomes, Malaria, Plasmodium, Targeted drug delivery, Heparin, Malaria, Plasmodium, Red blood cell, Targeted drug delivery, Liposomes, 1,2 dioleoyl 3 trimethylammoniopropane, fluorescein, heparin, liposome, nanoparticle, primaquine, adsorption, animal experiment, anticoagulation, antimalarial activity, Article, binding affinity, confocal microscopy, controlled study, drug targeting, encapsulation, erythrocyte, female, fluorescence microscopy, human, human cell, in vivo study, liposomal delivery, mouse, nonhuman, Plasmodium falciparum, transmission electron microscopy


Fernàndez-Busquets, X., (2013). Amyloid fibrils in neurodegenerative diseases: villains or heroes? Future Medicinal Chemistry 5, (16), 1903-1906

Fernàndez-Busquets, X., (2013). Heparin-functionalized nanocapsules: Enabling targeted delivery of antimalarial drugs Future Medicinal Chemistry 5, (7), 737-739

Urban, Patricia, Estelrich, Joan, Cortés, Alfred, Fernàndez-Busquets, X., (2011). A nanovector with complete discrimination for targeted delivery to Plasmodium falciparum-infected versus non-infected red blood cells in vitro Journal of Controlled Release 151, (2), 202-211

Current administration methods of antimalarial drugs deliver the free compound in the blood stream, where it can be unspecifically taken up by all cells, and not only by Plasmodium-infected red blood cells (pRBCs). Nanosized carriers have been receiving special attention with the aim of minimizing the side effects of malaria therapy by increasing drug bioavailability and selectivity. Liposome encapsulation has been assayed for the delivery of compounds against murine malaria, but there is a lack of cellular studies on the performance of targeted liposomes in specific cell recognition and on the efficacy of cargo delivery, and very little data on liposome-driven antimalarial drug targeting to human-infecting parasites. We have used fluorescence microscopy to assess in vitro the efficiency of liposomal nanocarriers for the targeted delivery of their contents to pRBCs. 200-nm liposomes loaded with quantum dots were covalently functionalized with oriented, specific half-antibodies against P. falciparum late form-infected pRBCs. In less than 90 min, liposomes dock to pRBC plasma membranes and release their cargo to the cell. 100.0% of late form-containing pRBCs and 0.0% of non-infected RBCs in P. falciparum cultures are recognized and permeated by the content of targeted immunoliposomes. Liposomes not functionalized with antibodies are also specifically directed to pRBCs, although with less affinity than immunoliposomes. In preliminary assays, the antimalarial drug chloroquine at a concentration of 2 nM, >= 10 times below its IC50 in solution, cleared 26.7 ± 1.8% of pRBCs when delivered inside targeted immunoliposomes.

Keywords: Antimalarial chemotherapy, Chloroquine, Half-antibodies, Immunoliposomes, Malaria, Nanomedicine


Urban, Patricia, Estelrich, Joan, Adeva, Alberto, Cortes, Alfred, Fernàndez-Busquets, X., (2011). Study of the efficacy of antimalarial drugs delivered inside targeted immunoliposomal nanovectors Nanoscale Research Letters 6, (1), 620

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: Plasmodium falciparum, Antimalarial drug, Nanovector, Immuno-liposomes