Investigating the potential of Ra-223 to combat Staphylococcus aureus in periprosthetic joint infections

Abstract

Periprosthetic joint infections by antibiotic-resistant biofilm-forming pathogenic bacteria such as Staphy-lococcus aureus are a growing concern in the field of arthroplasty. They are difficult to treat and can lead to implant revision surgery, health complications, and in some cases death. An established method in clinical practice for delivering antibiotics directly to the site of surgery is the use of antibiotic-loaded polymethyl methacrylate (PMMA), a synthetic polymer used to integrate joint implants into bone tissue. With rising rates of antibiotic resistance, researchers are looking for alternative treatments for bacterial infections and one of the possible candidates is targeted alpha therapy (TAT). Ra-223 is one such alpha emitter which is already being used in a clinical setting under the name Xofigo®to treat cancer. With the ability of PMMA to be loaded with pharmaceuticals, it may be worthwhile to investigate whether radioistopes such as Ra-223 can also be loaded and released from the polymer. In this thesis, the potential use of PMMA as a radioisotope delivery vehicle is investigated, as well as the bactericidal capacity of Ra-223 against S. aureus are investigated.
To achieve this, PMMA was loaded separately with two different radioisotopes, Ga-68 and Ra-223. The loading was done with and without the presence of a chelator. The release of the isotopes from PMMA was measured over time. Growth of S. aureus cultures was measured under different activities of Ra-223 and growth curves were constructed. The uptake of Ra-223 by the bacteria was also measured.
A minimum of 50% Ga-68 was found to be released when freely added to PMMA. This was due to the insolubility of the Ga-68 eluate in PMMA, causing the isotope to be concentrated in a single spot. However, the addition of a chelator significantly dampened the release to maximum of 3%, since Ga-68 was homogeneously dispersed throughout the PMMA volume. Ra-223 was shown to have a similar release when added freely to PMMA (47%), but the chelator used was shown not to extract any Ra-223 to the PMMA and therefore no release was observed. There was no measurable bactericidal effect of Ra-223 on S. aureus for the activities used in the experiments. It was found that 8±5% of the total amount of Ra-223 was taken up by the bacteria after 18 h of incubation.
Although PMMA seems to exhibit some radioisotope release, further experiments need to be carried out to determine if these amounts can evoke a bactericidal effect. The percentage of Ra-223 taken up by S. aureus shows that the isotope has some promise as a potential bactericide against it, but experiments with higher activities need to be carried out. Furthermore, future experiments are needed to determine the internalization of Ra-223 by S. aureus.