In a new study, researchers at the U.K.'s University of Liverpool and Johns Hopkins University School of Medicine in Baltimore have jointly developed a new long-acting nanomedicine-based delivery system for preventing malaria.
Malaria represents a significant burden of disease, with the most deadly form, Plasmodium falciparum, infecting more than 200 million people worldwide and killing around 650,000 each year.
Despite considerable success in reducing the prevalence of malaria, its incidence, including in visitors to endemic areas, has continued to increase steadily.
"There is currently no completely effective vaccine for malaria and no single totally reliable approach to prophylaxis," said co-lead researcher Andrew Owen, a professor in the University of Liverpool's Department of Molecular and Clinical Pharmacology.
"Daily oral administration of antimalarial drugs is currently used for prophylaxis but must be combined with other strategies such as insect repellent, appropriate clothing and using insecticide-treated bed nets," Owen told BioWorld.
The best currently available means of pharmacological malaria prophylaxis are antimalarial tablets. However, healthy people must be strictly compliant with those to achieve effective prophylaxis.
"Although antimalaria drugs exist, they require individuals to take the medication daily," said study co-lead researcher Steve Rannard, a professor in the University of Liverpool's Department of Chemistry.
However, "chronic oral dosing has significant complications arising from the high pill burden of many patients across populations with varying conditions leading to non-adherence with preventative therapies," Rannard told BioWorld.
The objective of the new study was to use nanotechnology to improve existing antimalarial drug delivery in a novel injectable form, which could maintain blood drug concentrations long after a single dose.
Nanotechnology involves manipulating matter on an atomic, molecular and supramolecular scale, for use in the diagnosis, prevention or treatment of disease.
Solid drug nanoparticles (SDNs) are one such nanotechnology that can help enhance drug exposure and improve treatment or prevention of diseases, including HIV and malaria.
The Liverpool team had previously shown SDNs to be effective for oral drug delivery, but this is the first time they have shown benefits for a long-acting injectable (LAI) format. Injected intramuscularly, SDNs establish a drug depot, releasing medicine into the bloodstream over an extended period.
Using that technology, the trans-Atlantic research team developed an LAI version of the daily antimalarial oral atovaquone (Mepron, Glaxosmithkline plc).
Mice injected intramuscularly with the nanomedicine achieved prophylactic blood concentrations and were completely protected from malaria for 28 days, the researchers reported in the Jan. 22, 2018, online edition of Nature Communications.
"Mice were injected with the SDN atovaquone formulation, and after 28 days mice were intravenously exposed to P. berghei sporozoites. They were then monitored for 42 days for parasites, and if none were seen, deemed to be protected, while none of the control mice were protected," said Owen.
"P. berghei strain Anka is an accepted preclinical model for malaria because mice cannot be infected with P. falciparum, which is restricted to great apes and humans," he explained. "Current oral medicines containing atovaquone are active against P. falciparum and P. vivax malaria, although possibly only primary infection by the latter. However, since our nanotechnology does not alter the drug's chemistry, one would expect efficacy against these strains to depend upon achievable blood concentrations after administration," said Owen.
"This is the first demonstration of LAI delivery using SDNs created using our proprietary approach of emulsion-templated freeze-drying" (ETFD), he said.
Owen pointed out that while LAI formulations have been developed for indications such as contraception, schizophrenia and HIV, "we believe ETFD has a number of explicit benefits, including compatibility with preferred agents, scalability and cost."
Since mice eliminate atovaquone more rapidly than do humans, a longer duration of protection might be expected in people. "Although our formulations achieved 28 days protection in mice, the half-life in humans is eight times slower than in mice, so the protection will almost certainly be longer than 28 days," said Owen.
"Our research seeks to remove the need for daily tablets and generate long-acting dosing technologies that may be able to provide therapeutic drug concentrations for months after a single administration," said Rannard.
"This would provide a clinically relevant intervention that could readily impact large numbers of people and significantly prevent transmission of malaria," he added.
"This ability to protect from malaria infection may provide an additional tool in the arsenal used to combat malaria in non-immune travelers and residents of endemic areas," noted Owen.
"Since atovaquone is already licensed for use in humans and the nanomedicine contains excipients to stabilize the formulations that are already used in other medicines, it could enter clinical trials within a very short timescale," he predicted. "As an academic group, our main barrier is funding to take the formulation forward, but our trans-Atlantic collaboration has the expertise to scale the formulations and conduct clinical trials, which with sufficient resources could begin within 18 to 34 months."
Owen noted that while studies have shown that atovaquone alone is an effective prophylaxis against malaria, drug combinations are required in patients already infected with the parasite, most commonly atovaquone plus proguanil. (See BioWorld Today, March 21, 2013.)
However, "proguanil doesn't lend itself well to this nanotechnology so we may need to be creative," he said. "If other drugs can be manufactured in this way, there is also potential for a long-acting combination therapy for malaria."