Abstract
BackgroundUse of chloroquine, an otherwise safe and relatively affordable anti-malarial drug, was discontinued due to widespread prevalence of resistant parasites. Many entrant anti-malarial drugs for treatment of chloroquine resistant malaria raises the concerns of cost and safety among other challenges. Innovative ways of circumventing chloroquine resistance is of paramount importance. Such may include nanoparticulate delivery strategies and targeting. This study evaluated physicochemical properties and in vitro antiplasmodial activity of chloroquine encapsulated heparin functionalized solid lipid nanoparticles (CQ-Hep-SLNs) and non-heparin functionalized SLNs (CQ-SLN) against Plasmodium falciparum.MethodsThe modified double-emulsion solvent evaporation technique was used to prepare the nanoparticles. HPLC/UV was used to determine the in vitro drug release. The semi-automated micro-dilution technique was adapted in assessing the in vitro antiplasmodial activity to give drug concentration capable of inhibiting 50% of the P. falciparum (IC50), as a function of antiplasmodial efficacy.ResultsPrepared nanoparticles were below 500 nm in size with % drug loading (%DL) between 21 and 25% and encapsulation efficiency (%EE) of 78–90%. The drug-loaded SLN exhibited a biphasic drug release profile at pH 7.4, with an initial burst release during the first 24 h followed by sustained release in both formulations. Nanoformulated CQ-SLN (4.72 ± 0.14 ng/mL) and CQ-Hep-SLN (2.41 ± 0.27 ng/mL), showed enhanced in vitro antiplasmodial activities against chloroquine sensitive (D6) strain of P. falciparum, albeit with no activity against the chloroquine resistant W2 strain, compared to free CQ standard (5.81 ± 0.18 ng/mL).ConclusionsThese findings suggest that the nanoformulated drugs displayed enhanced anti-malarial activities against chloroquine sensitive (D6) strains of P. falciparum compared to the free CQ standard. There is some form of potential dual synergistic effect of CQ-loaded heparinized solid lipid nanoparticles (Hep-SLN), meaning that combining heparin and CQ in SLNs has beneficial effects, including potential for specific targeting of parasitized red blood cells as afforded by heparin. Thus, the study has produced SLNs nanoparticles that have superior in vitro activities than CQ on CQ-sensitive parasites.
Highlights
Use of chloroquine, an otherwise safe and relatively affordable anti-malarial drug, was discontinued due to widespread prevalence of resistant parasites
Mortality due to malaria stood at 429,000 deaths worldwide in 2015, with 90% of these occurring in sub-Saharan Africa and the majority being children under 5 years of age [2]
The empty solid lipid nanoparticle (SLN) had a significantly bigger size (482.2 ± 12.0 nm) and zeta potential (24.0 ± 0.321 mV) compared to all the other prepared nanoparticles. This trend was expected since the empty SLN lack the electrostatic interaction expected between the positively charged chitosan and the negatively charged species (CQ-diphosphate and heparin), the bigger size and the large positive surface charge
Summary
An otherwise safe and relatively affordable anti-malarial drug, was discontinued due to widespread prevalence of resistant parasites. Innovative ways of circumventing chloroquine resistance is of paramount importance Such may include nanoparticulate delivery strategies and targeting. The high morbidity and mortality in sub-Saharan Africa are due to Plasmodium falciparum, the most virulent of the five malarial parasites that infect humans. Successful malaria elimination is still a challenge in the absence of new vaccines, drugs and vector control strategies. In the absence of an effective vaccine, chemotherapy is the only option readily available for managing malaria Much of this morbidity and mortality could be avoided if drugs available to patients were efficacious, of high quality and used correctly [7]. Due to the widespread prevalence of chloroquine-resistant (CQR) parasite strains, CQ was replaced as the front-line anti-malarial chemotherapy in the late 1990s. One possible strategy is to reformulate the available anti-malarials in an innovative way and nanotechnology has emerged as the best way of delivering the drugs to target site while potentially mitigating resistance [13, 14]
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