Therapeutic peptides that can cross the blood-brain barrier have been designed
Antimicrobial nanoparticles that can cross the, almost impermeable, blood-brain barrier have been created by Asian researchers. This may lead to better treatment for human brain infections such as meningitis and encephalitis, say the team.
Conventional antibiotics do not damage cell walls, but penetrate microbes to target specific actions such as cell division. However, with its morphology persevered, the microbe is still able to develop resistance. For this reason, many researchers have been investigating an alternative: antimicrobial peptides. These peptides do not have specific targets, and instead damage the membranes of microbes through an electrostatic interaction. This damage is hard to repair, and so resistance is prevented. These peptides are particularly useful for combating multidrug resistant microbes.
Now, a team led by Yi-Yan Yang, at the Institute of Bioengineering and Nanotechnology in Singapore, has found a way to make these antimicrobial peptides into nanoparticles that can cross the blood-brain barrier - a network of capillaries that often blocks the entry of therapeutic agents into the brain.
’Other types of nanoparticles have been reported to deliver drugs and imaging agents across the blood-brain barrier,’ says Yang. However, these are the first nanoparticles with strong antimicrobial activity to cross over, she adds. ’This is important because these nanoparticles may provide an effective treatment for brain infections that are caused not only by bacteria, but also by fungi and yeast.’
First the researchers designed a short peptide that contains a hydrophilic cell-penetrating peptide (called a Tat peptide), arginine residues (which aid membrane translocation), hydrophobic cholesterol (to drive the peptides’ self-assembly into core-shell nanoparticles) and glycine units that act as spacers. The team found that this peptide easily self-assembles to form nanoparticles.
These particles were then tested in vitro against a broad spectrum of microbes, and found to be ’more potent’ than their unassembled peptide counterparts. Next, the group tested their nanoparticles on mice infected with the bacterium Staphylococcus aureus - which can cause meningitis - and again showed very encouraging results. Moreover, in samples of brain tissue taken from infected rabbits that had also been treated, they found the nanoparticles had been able to pass the blood-brain barrier and suppress the growth of bacteria in the brain.
Yechiel Shai, an expert in interactions between peptides and microbes at the Weizmann Institute of Science in Rehovot, Israel, lauds the work. ’The study is the result of an elegant combination of information [the researchers] have gained during the past few years,’ he told Chemistry World. ’They were able to deliver the compound to its target, which is the major task in using antimicrobial peptides for therapy,’ he adds.
Shai did warn, however, that a major question remains: ’how to cross the bridge and develop them for human health.’ This is a hurdle that none of the other promising antimicrobial peptides reported during the past two decades or more have overcome, he explains. Yang’s group are planning to attempt this, performing preclinical trials in the near future and then applying to the US Food and Drug Administration to enter clinical trials.
Yi-Yan Yang et alNature Nanotech., 2009, DOI: 10.1038/nnano.2009.153