Najer, Adrian. Nanotechnological solutions to combat Malaria. 2016, PhD Thesis, University of Basel, Faculty of Science.
Restricted to Repository staff only until 1 July 2018.
Official URL: http://edoc.unibas.ch/diss/DissB_11791
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.
|Advisors:||Meier, Wolfgang P. and Palivan, Cornelia G. and Beck, Hans-Peter and Pandit, Abhay|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Klinische Pharmazie/Spitalpharmazie (Meier)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||1 Online-Ressource (XII, 156 Seiten)|
|Last Modified:||23 Sep 2016 09:28|
|Deposited On:||23 Sep 2016 09:28|
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