Exploring medical applications of a bioactive polymer
Abstract: In this thesis, we have studied a polymeric compound called PVAC, designed as a scavenger of reactive electrophilic substances. We explored several diseases where these substances are overproduced.In Paper I, adhesion formation was induced via bowel anastomosis surgery in rats. Formation of adhesions is a process driven by hypoxia and reactive electrophilic substances; we hypothesised that PVAC could stop the processes if administered peri-surgery. PVAC was administered in two different ways, as a peritoneal lavage post-surgery and as an addition to the sutures used during the surgery. When sutures were impregnated with PVAC before surgery, weaker adhesion formation was observed at the surgery site. No difference was noted between PVAC treated and control animals when it was delivered via lavage. Another situation where electrophiles are a problem was studied in Paper II, haemolysis. Haemolysis in vitro is a process driven by oxidative processes during the storage of red blood cells. When storage media was supplemented with PVAC, a dose-dependent decrease in haemolysis and increased red blood cell stability was observed.In Paper III, we investigated the effects of PVAC as an anti-tumoural agent based on observations in cell cultures. When cell lines were cultured in the presence of PVAC, a reduction in viability of cells was observed. When PVAC was studied in animal models, we found an effect of the polymer in melanoma in immunocompetent mice but not in breast cancer in athymic mice. When tumour biopsies were studied, increased T cell infiltration was noted in PVAC treated animals. An immune-mediated mechanism might explain why no effect was seen in the athymic mice since they lack an adaptive immune system.In Paper IV, we labelled PVAC using a radioactive tracer, [18F]FBA, to detect PVAC in a PET camera. Rats underwent surgery to induce ischaemia reperfusion injury in kidneys or limbs. [18F]FBA PVAC accumulated in the ischaemic tissue after I.V administration, it was possible to distinguish the injured area after 20 minutes. Since reactive electrophiles are also mediators of disease in ischaemia reperfusion injury we aim to investigate if PVAC has therapeutic potential in addition to the ability to detect ischaemia.To conclude, we have explored PVAC as an example of a bioactive polymer. We feel that the compound group is underused in medicine that we hope this thesis will prime more researchers to explore.
CLICK HERE TO DOWNLOAD THE WHOLE DISSERTATION. (in PDF format)