PLGA TIPS microparticles loaded with oxidative precursor species tetraacetylethylenediamine (TAED).
PLGA TIPS microparticles loaded with oxidative precursor species tetraacetylethylenediamine (TAED).

The rise of antibiotic-resistant bacteria urgently demands new treatments that can prevent the spread of infection. As an alternative to conventional antibiotics, which are susceptible to resistance, oxygen-containing chemical species with well-recognized biocidal properties are being re-evaluated. Now researchers from University College London and GAMA Healthcare Ltd have developed biodegradable microparticles that release high-energy oxidative species in a safe and controlled way [Sofokleous et al., Acta Biomaterialia (2017), doi: 10.1016/j.actbio.2017.10.001,].

Oxidative species hydrogen peroxide (H2O2) and peracetic acid (PAA) can effectively combat even drug-resistant bacteria, but also damage healthy tissue. While controlled delivery of toxic agents has received much attention in chemotherapy to minimize side effects, the same approach has proved difficult to apply to oxidative species. The typical polymeric microparticles used to deliver active agents are commonly manufactured in a process that involves a ‘washing’ step to remove surplus solvent. Precursors of oxidative species, however, are extremely sensitive to such ‘wet’ conditions and rapidly decompose into other products. These handling issues have prevented the serious consideration of oxidative species as therapeutic replacements for conventional antibiotics until now.

Richard M. Day and his colleagues turned to an alternative manufacturing method called thermally induced phase separation (TIPS), a ‘dry’ process which employs freeze-drying (or lyophilization) instead of washing, to produce microparticles. Using the same biodegradable material as surgical sutures, poly(lactic-co-glycolic) (PGLA) microparticles are loaded with oxidative precursor species tetraacetylehtylenediamine (TAED) and sodium percarbonate (SP). When the microparticles are exposed to aqueous conditions, such as in a wound or inside the body, the polymer degrades releasing the precursor species, which react to produce H2O2 and PAA.

The novel approach successfully killed typical Gram-positive and Gram-negative bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant Escherichia coli in lab tests and did not damage cells or tissue when applied to pre-clinical models.

“Our results demonstrate, for the first time, the ability to load precursor compounds that are released and converted into oxidative species in a controlled manner,” says Day. “The approach is novel and potentially transformative in that the biodegradable microparticles can be engineered to exhibit a wide range of physical and biological properties tailored to specifically target a given organ or infection site.”

As well as controlling the amount of precursor, degradation and release properties, the microparticles could also be optimized for pulmonary, oral or systemic delivery.

“The ultimate impact could be the creation of a new family of materials-based anti-infective chemotherapeutic agents with the capability of acting on a wide range of infections with minimal potential for giving rise to acquired microbial resistance,” suggests Day.

Further investigation is now needed to see if the approach is effective in pre-clinical models that mimic typical clinical infection scenarios.