Macrophage selective photodynamic therapy by meta-tetra(hydroxyphenyl)chlorin loaded polymeric micelles: A possible treatment for cardiovascular diseases

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.

π-π-Stacked Poly(ε-caprolactone)-b-poly(ethylene glycol) Micelles Loaded with a Photosensitizer for Photodynamic Therapy

“…However, in a recent study, we showed a rapid release of this PS in the circulation after i.v. administration of the mTHPC-loaded PCL-PEG-based micelles [24]. The poor stability in the circulation is currently considered a limitation for micelles for successful clinical applications [24][25][26][27].…”

“…administration of the mTHPC-loaded PCL-PEG-based micelles [24]. The poor stability in the circulation is currently considered a limitation for micelles for successful clinical applications [24][25][26][27]. This instability is most likely due to a combination of extraction of the cargo from the micelles and micellar destabilization resulting from a large dilution volume upon injection or binding of drug-polymer chains to blood components (e.g., albumin, lipoproteins) [28].To overcome their inherent instability, physical interactions through π-π stacking have been investigated to enhance the stability of polymeric micelles.…”

The Surface Modification Methods for Constructing Polymer-Coated Stents

“…Among them, cardiovascular disease has being listed as a major cause of death and morbidity globally based on the status report of noncommunicable diseases in the world [1,[3][4][5][6][7]. Atherosclerosis, as a chronic inflammation with slow progressive buildup of lipids and macrophages within the arterial wall, is the primary contributor to myocardial infarctions and atherosclerotic plaque rupture [1,8]. In comparison with an open-heart surgery, angioplasty exhibits more benefits to patients and has been extensively employed to treat atherosclerosis by implanting an antithrombogenic agent-coated stent into the infected lesion in order to maintain an artery open after balloon angioplasty [3,9]; moreover, general anesthesia is unnecessary for patients.…”

“…Among them, cardiovascular disease has being listed as a major cause of death and morbidity globally based on the status report of noncommunicable diseases in the world [1,[3][4][5][6][7]. Atherosclerosis, as a chronic inflammation with slow progressive buildup of lipids and macrophages within the arterial wall, is the primary contributor to myocardial infarctions and atherosclerotic plaque rupture [1,8].…”

“…Developing technologies is an urgent need to treat coronary artery diseases induced by generic factors and dietary habits [1,2]. Among them, cardiovascular disease has being listed as a major cause of death and morbidity globally based on the status report of noncommunicable diseases in the world [1,[3][4][5][6][7].…”