Abstract
Cardiovascular diseases are the leading causes of death world wide. The present
IVUS and angiography techniques cannot suciently distinguish between stable
atheromatous lesions and vulnerable plaques. Furthermore, the present cardiovascular
drugs can only slow down the processes involved in atherosclerosis, but they
cannot remove or stabilize dangerous vulnerable plaques satisfyingly. This thesis
describes the development of a theranostic dendrimer-based nanoparticle system
for the detection (imaging) of vulnerable atheromatous plaques and their treatment/
stabilization by means of photodynamic therapy. For this purpose, a dendrimer
nanoparticle system was developed that showed promising cytotoxicity and
immunogenicity. These dendrimers were capable of solvating lipophilic phthalocyanines,
which are second-generation photosensitizers. The dendrimer phthalocyanine
conjugates had light emission and excitation spectra within the biological window
for in vivo imaging, which can be used for 2D near-infrared uorescence molecular
imaging (2D-NIRF). Furthermore, the compounds expressed no detectable darktoxicity;
however, radiation of the compound with light of the right wavelength
(670 nm) triggered the formation of singlet oxygen and enabled photodynamic therapy.
In vivo studies in mice and rabbit models showed that the dendrimer phthalocyanine
formulations could target the macrophage-rich plaque areas, which are the
most vulnerable and dangerous plaques. No localization of the compound in the
healthy endothelium was found, which is a necessity in order to successfully treat
a patient without injuring healthy tissue. The high uorescence intensity and the
selective targeting of the plaques enabled in vivo 2D-NIRF imaging using an angioplasty
rabbit model. Photodynamic therapy studies were successfully carried out in
vitro, and in vivo studies are in progress with highly promising initial data. The dendrimer
phthalocyanine nanoparticle system was nally chosen by the Consortium
of the FP-7 large-scale project CosmoPHOS-nano to be translated into a clinical
phase I study in human patients and is currently under preclinical development.
IVUS and angiography techniques cannot suciently distinguish between stable
atheromatous lesions and vulnerable plaques. Furthermore, the present cardiovascular
drugs can only slow down the processes involved in atherosclerosis, but they
cannot remove or stabilize dangerous vulnerable plaques satisfyingly. This thesis
describes the development of a theranostic dendrimer-based nanoparticle system
for the detection (imaging) of vulnerable atheromatous plaques and their treatment/
stabilization by means of photodynamic therapy. For this purpose, a dendrimer
nanoparticle system was developed that showed promising cytotoxicity and
immunogenicity. These dendrimers were capable of solvating lipophilic phthalocyanines,
which are second-generation photosensitizers. The dendrimer phthalocyanine
conjugates had light emission and excitation spectra within the biological window
for in vivo imaging, which can be used for 2D near-infrared uorescence molecular
imaging (2D-NIRF). Furthermore, the compounds expressed no detectable darktoxicity;
however, radiation of the compound with light of the right wavelength
(670 nm) triggered the formation of singlet oxygen and enabled photodynamic therapy.
In vivo studies in mice and rabbit models showed that the dendrimer phthalocyanine
formulations could target the macrophage-rich plaque areas, which are the
most vulnerable and dangerous plaques. No localization of the compound in the
healthy endothelium was found, which is a necessity in order to successfully treat
a patient without injuring healthy tissue. The high uorescence intensity and the
selective targeting of the plaques enabled in vivo 2D-NIRF imaging using an angioplasty
rabbit model. Photodynamic therapy studies were successfully carried out in
vitro, and in vivo studies are in progress with highly promising initial data. The dendrimer
phthalocyanine nanoparticle system was nally chosen by the Consortium
of the FP-7 large-scale project CosmoPHOS-nano to be translated into a clinical
phase I study in human patients and is currently under preclinical development.
| Original language | English |
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| Publisher | Department of Chemistry, Faculty of Science, University of Copenhagen |
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| Number of pages | 225 |
| Publication status | Published - 2016 |
