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Novel strategies for Plasmodium-targeted drug delivery

The disappointing repeated failure of the therapeutic arsenal deployed against Plasmodium since the identification in 1880 by Alphonse Laveran of this protist as the causing agent of malaria calls for a radical shift in the way we approach the treatment of this disease. To counteract the evolution of Plasmodium resistance to antimalarial drugs and their resulting loss of efficacy,[1] three main protocols have been traditionally followed: development of new compounds, increase of dosage, and the introduction of drug combinations. New antimalarial drugs are being discovered at an excruciatingly slow pace, far below the rhythm at which resistant pathogen strains emerge. Apart from few remarkable exceptions,[2] there is a clear lack of sufficient economic resources allocated to the research of new agents against infectious diseases which are not prevalent in the developed world. This trend does not seem likely to be reversed if we consider the poor prospects for a profit-seeking industry of obtaining high gains through investments in treatments to be mainly used in developing areas of the world, whereas public funding is also biased toward those diseases more directly affecting the citizens of the countries with the highest gross national products (i.e. those usually having a larger research budget). The second approach of simply administering higher antimalarial drug amounts usually results either in side effects severe enough to discourage people from taking the medicine or in the need to take several doses, which is often not fulfilled; such patient noncompliance is one of the main triggers of drug resistance evolution.[3] Finally, drug combinations can delay the selection of multiple resistance,[4] which, however, will eventually occur, ending up in loss of efficacy of even the most promising frontline drugs.[5] This scenario calls for urgent new approaches capable of breaking a century-long monotony of antimalarial therapeutics. Rather than focusing all efforts on identifying new drugs whose efficacy is rapidly diminished by the parasite’s evolution of resistance, an important and often disregarded battlefront is the implementation of targeted delivery methods capable of increasing the doses reaching the pathogen up to local levels sufficiently high to minimize this resistance emergence. Regrettably, the search for this long sought-after magic bullet against malaria has not taken off in earnest yet. However, recent data outline the feasibility of some such potential novel approaches, among which we can count (i) new types of combination therapies where one of the activities does not act on individual Plasmodium gene products, (ii) the prophylactic preloading of uninfected erythrocytes with antimalarial drugs to prevent entry of the pathogen in its host cell, and (iii) targeting Plasmodium stages in the mosquito vector, an underexplored strategy whose foreseeable benefits clearly outweigh the evident obstacles hampering its implementation.