Nanotechnological solutions to combat Malaria

Infectious diseases remain a major cause of death worldwide, despite enormous control efforts. A major problem in the context of antimicrobial drug resistance, which already leads to treatment failures, is the lack of novel antimicrobial drugs. Further, current and future control measures are threatened by the inexistence, unavailability, and failures of vaccines. In this regard, development of novel tools, including new antimicrobial drugs, vaccines, alternative drug/vaccine delivery systems, and other strategies, is urgently needed to keep up the fight against infectious diseases. Malaria is a typical example of an infectious disease to which the above-mentioned problems apply. This disease is caused by Plasmodium spp. parasites that are transmitted by Anopheles mosquitoes. The life cycle of malaria parasites in humans involves a blood stage cycle that is responsible for disease pathogenesis and includes continuous red blood cell (RBC) invasion, asexual multiplication, and subsequent egress of parasites back into the bloodstream.
In this thesis, two alternative nanotechnological strategies aimed at the malaria blood stage cycle are presented. Both of these strategies are considered valuable alternatives for malaria treatment/prophylaxis compared to conventional drug treatment and experimental vaccination schemes. The first ‘nanomimic strategy’ aims for a dual drug- and "vaccine-like" action using RBC membrane-mimicking nanostructures, termed ‘nanomimics’. The drug action is the inhibition of parasite invasion into RBCs by these nanomimics. "Vaccine-like" activity is achieved through generation of an immune response by exposed extracellular parasites bound to nanomimics as obtained during the drug action. Several amphiphilic block copolymers were designed and synthesized that contain a RBC receptor molecule that is known to be used by the parasite to attach to RBCs. These functional block copolymers were mixed with another type of block copolymer to prepare polymer vesicles (polymersomes) by self-assembly, which served as nanomimics and giant RBC membrane models. Highly potent invasion-inhibitory nanomimics were realized following this procedure as determined by in vitro assays using malaria blood stage cultures in suspension. Further analyses revealed binding of multiple nanomimics to one parasite and multivalent, high-affinity interaction of receptor molecules on nanomimics with a corresponding parasite ligand. Potential adverse effects of nanomimics related to cellular toxicity, anticoagulation property, and endotoxin contamination, were found to be negligible. Preliminary tests on the second "vaccine-like" activity point in a promising direction, but this needs to be further studied in more detail. A potential application of nanomimics is treatment and immune boost for children having one of their first infections, in order to induce protection from subsequent infections. Furthermore, many human pathogens use the same receptor molecule to interact with target cells that is currently presented on the nanomimics prepared in the scope of this thesis. Therefore, the nanomimic strategy has the potential to be directly applied to other infectious diseases, too.
In the second approach, the delivery of a poorly soluble, metabolically instable antimalarial drug candidate to Plasmodium-infected RBCs (iRBCs) using functional nanoparticles was examined. For this purpose, a reduction-responsive, degradable, polymeric nanoparticle platform was successfully designed and applied. The highly reducing cytosol environment of iRBCs acts as the trigger for nanoparticle disassembly and subsequent drug release. In contrast, these loaded nanoparticles were stable in extracellular environments. This drug delivery platform is promising in tackling antimalarial resistance, and to deliver any hydrophobic antimicrobial drug candidate at early development stages to corresponding diseased cells.