AGA Nanotech, a medtech company based in the UK, has developed nanotechnologies aimed at overcoming antimicrobial resistance, with a view to offering an alternative to conventional antibiotics. The company has collaborated with researchers from University College London to create poly(lactic-co-glycolic acid) (PLGA) nanoparticles that can deliver highly oxidative biocides, using a Thermally Induced Phase Separation (TIPS) technique to load the particles.
The nanoparticle payloads consist of precursors for hydrogen peroxide and peracetic acid. These oxidative components are toxic to many antibiotic-resistant bacteria, but break down to relatively benign residues, and so could minimize side-effects in human tissues. The company is currently conducting in vitro and in vivo tests, including preliminary safety and efficacy studies, and their first planned application for the treatments is a topical therapy to aid in wound healing. However, other routes of delivery may also be possible, including systemic, oral, or pulmonary delivery.
Medgadget asked Adrian Fellows, Head of R&D at AGA Nanotech some questions about the system.
Conn Hastings, Medgadget: Please tell us a little about antibiotic resistance and the challenges it poses.
Adrian Fellows, AGA Nanotech: Bacteria are capable of developing mutations which make them resistant to the action of an antibiotic. The antibiotic usually has a very specific site of action. The widespread use of and misuse of antibiotics has given rise to bacteria which are resistant to several types of antibiotics. These are the so-called MDROs – multi drug resistant organisms. The threat of increased antibiotic resistance has been identified as possibly the major healthcare threat facing mankind. If nothing is done to replenish the pipeline of antimicrobial treatments, it is estimated that by 2050 more than 10 million deaths per annum would be caused by resistant bacterial infections and much of modern surgery would be impossible. Minor injuries could once again prove fatal.
Medgadget: How does the approach adopted by AGA Nanotech in treating drug-resistant infections mirror approaches used in oncology?
Fellows: Government and funding bodies have pointed to the necessity of “outside the box” thinking to solve the antimicrobial resistance problem. AGA proposes the delivery to the site of infection of precursors for high energy oxidative biocides which do not give rise to resistance. These highly reactive chemicals could not normally be used therapeutically, because of collateral damage to the patient. The same problem is faced in oncology in delivering toxic anti-cancer drugs to tumors. We adapted this approach and use a nano or micro biodegradable particle to entrap the precursors and deliver them to the site of infection without harming the patient. At the infection site, precisely controlled release of the actives is possible which again attacks the infection without harming the patient.
Medgadget: How are the particles loaded? Can you describe the Thermally Induced Phase Separation technique?
Fellows: The particle polymer (PLGA) is dissolved in a solvent. This is mixed with a solution of the precursor molecule(s). The mixture is then passed through a microencapsulation unit and the particle/precursor complexes are collected under liquid nitrogen. They are then freeze-dried for storage.
Medgadget: So, how does the nanoparticle payload kill bacteria?
Fellows: The particle payload is made up of inert and safe precursors. At the site of infection, the precursors react with water in the physiological milieu to produce a dynamic equilibrium of hydrogen peroxide and peracetic acid. These high energy biocides act rapidly to kill a wide spectrum of bacteria but have very low systemic toxicity and also decay to simple benign metabolizable residues, as does the PLGA. The specific outcome can be bio-engineered very precisely over a wide range of parameters to suit the clinical situation.
Medgadget: How do the particles target bacteria, while sparing human tissues?
Fellows: This depends on the clinical target. In wound care, minimal specific targeting is required. Important parameters can be varied; for example, the proportion of initial burst release action versus longer term sustained release.
For systemic deep-seated infections, it may be necessary to coat the particles in different ways, for example pegylation or coatings to allow particles to reach the gut. To target a particular infection, the particles can be elaborated with targeting ligands, monoclonal antibodies, biosensors etc.
Medgadget: How does the therapy circumvent common resistance mechanisms? Could bacteria easily mount new resistance mechanisms against these oxidative treatments?
Fellows: The hypothesis tested was: if the problem is resistance, then use antimicrobials that do not give rise to resistance. Unlike antibiotics, the high energy oxidative biocides such as peracetic acid do not attack individual targets. They react with multiple sites and effectively tear the bacterial cell apart. Resistance has not been demonstrated to peracetic acid over the range of concentrations or timescales potentially available to this technology. Resistance to hydrogen peroxide is noted by catalase and dismutase enzymes, but not to the peracetic acid/peroxygen complex.
In the unlikely event of resistance appearing to a specific embodiment of this technology it would be readily overcome by adjustment of treatment parameters. Combinations of this technology with more conventional approaches could be envisaged.
Link: AGA Nanotech…