Abstract
Selective elimination of macrophages by photodynamic therapy (PDT) is a new and promising therapeutic modality for the reduction of atherosclerotic plaques. m-Tetra(hydroxyphenyl)chlorin (mTHPC, or Temoporfin) may be suitable as photosensitizer for this application, as it is currently used in the clinic for cancer PDT. In the present study, mTHPC was encapsulated in polymeric micelles based on benzyl-poly(ε-caprolactone)-b-methoxy poly(ethylene glycol) (Ben-PCL-mPEG) using a film hydration method, with loading capacity of 17%. Because of higher lipase activity in RAW264.7 macrophages than in C166 endothelial cells, the former cells degraded the polymers faster, resulting in faster photosensitizer release and higher in vitro photocytotoxicity of mTHPC-loaded micelles in those macrophages. However, we observed release of mTHPC from the micelles in 30min in blood plasma in vitro which explains the observed similar in vivo pharmacokinetics of the mTHPC micellar formulation and free mTHPC. Therefore, we could not translate the beneficial macrophage selectivity from in vitro to in vivo. Nevertheless, we observed accumulation of mTHPC in atherosclerotic lesions of mice aorta's which is probably the result of binding to lipoproteins upon release from the micelles. Therefore, future experiments will be dedicated to increase the stability and thus allow accumulation of intact mTHPC-loaded Ben-PCL-mPEG micelles to macrophages of atherosclerotic lesions.
Highlights
At present the world population encounters increase in age, obesity and lack of physical activity (Roger et al, 2012)
Acetonitrile, dimethyl sulfoxide (DMSO), trifluoroacetic acid, hydrogen peroxide, fetal bovine serum (FBS), trypsin, EDTA, PBS, ethanol, propylene glycol and high glucose Dulbecco modified eagle medium (DMEM) were obtained from Sigma-Aldrich (Zwijndrecht, the Netherlands). 384-Well plates were purchased from Fisher scientific GmbH (German)
Ben-PCL7-mPEG45 micelles prepared at 10 mg/mL polymer concentration had a size of 16 nm and a narrow size distribution, while the size increased to 57 nm for the largest Ben-PCL19-mPEG45 copolymers
Summary
At present the world population encounters increase in age, obesity and lack of physical activity (Roger et al, 2012) This can give imbalance in the human physiology leading to among others high blood pressure, diabetes and unhealthy cholesterol levels, which eventually cause cardiovascular diseases being the number one cause of death in the western world. When atherosclerosis is detected in a later phase it is mainly due to myocardial infarctions In this stage the options are more rigorous and are mainly focused on opening the vessel by balloon angioplasty (Gray and Sullivan, 1996) with or without stenting (Farb et al, 1999) and in the most severe cases a bypass vessel (Sarjeant and Rabinovitch, 2002) will be installed. Until now none of these methods are treating or removing the inflammation and reoccurrence of myocardial infarctions in atherosclerotic patients is high (Davidsen et al, 2002; Smolina et al, 2012)
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