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Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics.

Josefsen LB, Boyle RW - Theranostics (2012)

Bottom Line: Porphyrinic molecules have a unique theranostic role in disease therapy; they have been used to image, detect and treat different forms of diseased tissue including age-related macular degeneration and a number of different cancer types.Current focus is on the clinical imaging of tumour tissue; targeted delivery of photosensitisers and the potential of photosensitisers in multimodal biomedical theranostic nanoplatforms.The roles of porphyrinic molecules in imaging and pdt, along with research into improving their selective uptake in diseased tissue and their utility in theranostic applications are highlighted in this Review.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The University Of Hull, Kingston-Upon-Hull, HU6 7RX, U.K.

ABSTRACT
Porphyrinic molecules have a unique theranostic role in disease therapy; they have been used to image, detect and treat different forms of diseased tissue including age-related macular degeneration and a number of different cancer types. Current focus is on the clinical imaging of tumour tissue; targeted delivery of photosensitisers and the potential of photosensitisers in multimodal biomedical theranostic nanoplatforms. The roles of porphyrinic molecules in imaging and pdt, along with research into improving their selective uptake in diseased tissue and their utility in theranostic applications are highlighted in this Review.

No MeSH data available.


Related in: MedlinePlus

Scheme 1. Simplified Haem Biosynthesis.
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FS1: Scheme 1. Simplified Haem Biosynthesis.

Mentions: A number of different imaging systems exist which are capable of observing molecular, structural and functional parameters of the mammalian body. The type of imaging system is chosen depending on the spatial scale of the entity to be imaged and the source of contrast enhancement. For example, imaging at the molecular level, involving small molecules and proteins (ranging from 10ppm-10nm), can be achieved with spectroscopy-based techniques including MRS (magnetic resonance spectroscopy), PET and optical spectroscopy; such imaging techniques facilitate the visualisation, characterisation and quantification of biological targets and processes at a cellular level; particularly useful for the imaging of singlet oxygen 194. Microscopy, surgical microscopy, endoscopy, ultrasound and fluoroscopy techniques can be used for imaging organelles; cells; tissue matrices; physiological ducts; and tissue layers ranging in size from 50nm-100mm and are valuable platforms in surgical-guidance, therapy monitoring and dosimetry procedures 194. When images of body organs and the whole body are required tomographic techniques such as computerised tomography (CT) and MRI are employed 194. Imaging at the molecular level provides the ability to monitor in vivo responses to pdt in near/real-time 194. In many situations, the outcome of an oncological treatment is only known at a much later date when the patient is undergoing post-sampling protocols or when the disease may have progressed/recurred due to incomplete removal and/or poor treatment response; online and/or early monitoring approaches are invaluable in developing strategies to combat inadequate treatment responses - one strategy is the use of image-guided surgical-resection (achieved with autofluorescence bronchoscopy and/or DIF) 194. Due to the propensity of photosensitisers to preferentially accumulate in neoplastic tissue their fluorescence properties makes them inherently well-suited for the selective visualisation of tumours using the fluorescence contrast between healthy and diseased tissue to demarcate the boundaries around diseased sites. The ability to accurately define the margins of a tumour is a crucial step in the optimisation of surgical resection; a cancer-free margin around the cancerous tissue that is being excised is a major predictive factor in the success of the treatment and the long-term outcome for the patient 28, 183, 194. Particular care must be taken not to remove too much healthy tissue - this is most apparent in brain surgery, for example, if 1mm of tissue were unnecessarily excised motor skills could be detrimentally affected with severe implications to the patient's quality of life 194. The suitability of PSFD for clinical translation has allowed its use for selective identification of cancerous lesions in a broad range of anatomical sites including the lungs, bladder, brain, skin, breast and female reproductive tract 28, 183, 185, 188, 191, 193, 194, 198. The limitation of PSFD, particularly, in comparison to PET, MRI and CT, is the inherent surface sensitivity of the technique; PET, MRI and CT are able to provide structural details that are not achievable with PSFD - the detection sensitivity of PSFD decreases during the resection process as the volume of non-resected disease diminishes - the sensitivity of fluorescence imaging is not affected 194. PSFD had its first widespread and successful implementation in identifying diseased tissue after Kennedy and Pottier introduced an alternative approach of enhanced endogenous protoporphyrin (PPIX) production in the haem cycle of tumours in the early 1990s 231, 232. The strategy is based on the in situ conversion of ALA, a non-photoactivatable precursor, into PPIX, a naturally occurring photosensitising species via the cellular haem biosynthesis pathway (Figure S1/scheme 1). In the synthetic pathway iron is inserted into the PPIX cavity to form haem; the ferrochelatase enzyme that catalyses this chelation is down-regulated in many tumours and as a result iron is chelated into the PPIX cavity at a relatively low rate and is unable to compensate for the excess PPIX formed - significant accumulation of PPIX in neoplastic tissue occurs as a result following administration of exogenous ALA. The rates of ALA uptake in healthy verses neoplastic tissue are thought to be comparable; it is the differential rates of ALA conversion and resulting accumulation of PPIX that are the primary force behind favourable tumour selectivity 194, 233. PSFD has proved a powerful tool in the detection and guided resection of bladder cancer and has been reviewed by Witjes and Douglass 194, 234. Bladder cancer is the fourth most common malignancy in men and the industrial world; it has a high rate of recurrence and is a very costly cancer to treat and monitor 235-237. A critical factor in predicting disease recurrence is the detection of carcinomas in situ (CIS); these flat lesions are particularly difficult to detect with white light due to the poor contrast they generate 194, 236. Levulan® has proved successful in the fluorescence identification of numerous bladder lesions that were not detected by white light bronchoscopy; the detections were 100% supported by histological validation 194, 238-241. In the follow-up assessment of patients with fluorescence imaging, the superior sensitivity of the modality led to a reduced rate of early recurrence of superficial bladder cancer in comparison to white light evaluation 242. In a phase III trial, comparing transurethral guided resection using ALA verses white light cystoscopy, 61.5% of the patients in the PPIX fluorescence endoscopy group were tumour-free at the follow-up assessment in comparison to only 40.6% in the white light group 243. The hexylester derivative of ALA, Hexvix®, has been used to achieve greater tissue penetration depths into the urothelial layers and a more homogeneous distribution in malignant tissue; Hexvix® produced a stronger fluorescence intensity at a lower dose following a shorter incubation time 244. Fluorescence-guided resection (FGR) has also been used in the treatment of brain cancer; when ALA-induced PPIX was used in a guided resection study 63% of the patients achieved complete resection through contrast enhancement. A phase III trial was terminated at the interim analysis of 270 patients, when 65% of those in the FGR group (procedure followed by standard adjuvant radiotherapy) were free of residual disease at the post-operative 6 month assessment (by MRI), compared with 36% in the white light group. It is noted that the survival curves for the patients in both groups converged after 15 months 194, 245. Foscan®, particularly suited to imaging and treating bulky brain tumours due to its depth of light penetration, has been evaluated by Zimmermann and colleagues for the FGR of malignant gliomas; in 138 tissue specimens from 22 of the patients, a sensitivity and specificity of 87.9% and 95.7% were achieved 194, 246. In 10 of the 22 patients, malignancies were not identified by white light examination but were exclusively identified by PSFD 194, 246. Foscan® has exhibited further advantages over ALA-induced PPIX in that after several minutes of illumination it does not undergo photobleaching. To date, FGR has been invaluable in improving the extent to which tumour tissue can be removed but is now beginning to show promise in cases where a tumour cannot be completely removed because it has infiltrated functional brain tissue; the residual tumour tissue can be treated with pdt. In a standard treatment protocol, surgical resection is followed by adjuvant radiotherapy, however, when FGR is used instead of white light, the photosensitiser is already present in the tissue at the time of resection; a logical extension of the procedure would be to use pdt to selectively destroy any residual disease in the resection bed - a great example demonstrating the promise of theranostic regimens. Kostron and colleagues reported results from a study on FGR with adjuvant pdt in a group of patients (26) with malignant brain tumours using m-THPC; an increase in median survival from 3½ months to 9 months was achieved 247.


Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics.

Josefsen LB, Boyle RW - Theranostics (2012)

Scheme 1. Simplified Haem Biosynthesis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3475217&req=5

FS1: Scheme 1. Simplified Haem Biosynthesis.
Mentions: A number of different imaging systems exist which are capable of observing molecular, structural and functional parameters of the mammalian body. The type of imaging system is chosen depending on the spatial scale of the entity to be imaged and the source of contrast enhancement. For example, imaging at the molecular level, involving small molecules and proteins (ranging from 10ppm-10nm), can be achieved with spectroscopy-based techniques including MRS (magnetic resonance spectroscopy), PET and optical spectroscopy; such imaging techniques facilitate the visualisation, characterisation and quantification of biological targets and processes at a cellular level; particularly useful for the imaging of singlet oxygen 194. Microscopy, surgical microscopy, endoscopy, ultrasound and fluoroscopy techniques can be used for imaging organelles; cells; tissue matrices; physiological ducts; and tissue layers ranging in size from 50nm-100mm and are valuable platforms in surgical-guidance, therapy monitoring and dosimetry procedures 194. When images of body organs and the whole body are required tomographic techniques such as computerised tomography (CT) and MRI are employed 194. Imaging at the molecular level provides the ability to monitor in vivo responses to pdt in near/real-time 194. In many situations, the outcome of an oncological treatment is only known at a much later date when the patient is undergoing post-sampling protocols or when the disease may have progressed/recurred due to incomplete removal and/or poor treatment response; online and/or early monitoring approaches are invaluable in developing strategies to combat inadequate treatment responses - one strategy is the use of image-guided surgical-resection (achieved with autofluorescence bronchoscopy and/or DIF) 194. Due to the propensity of photosensitisers to preferentially accumulate in neoplastic tissue their fluorescence properties makes them inherently well-suited for the selective visualisation of tumours using the fluorescence contrast between healthy and diseased tissue to demarcate the boundaries around diseased sites. The ability to accurately define the margins of a tumour is a crucial step in the optimisation of surgical resection; a cancer-free margin around the cancerous tissue that is being excised is a major predictive factor in the success of the treatment and the long-term outcome for the patient 28, 183, 194. Particular care must be taken not to remove too much healthy tissue - this is most apparent in brain surgery, for example, if 1mm of tissue were unnecessarily excised motor skills could be detrimentally affected with severe implications to the patient's quality of life 194. The suitability of PSFD for clinical translation has allowed its use for selective identification of cancerous lesions in a broad range of anatomical sites including the lungs, bladder, brain, skin, breast and female reproductive tract 28, 183, 185, 188, 191, 193, 194, 198. The limitation of PSFD, particularly, in comparison to PET, MRI and CT, is the inherent surface sensitivity of the technique; PET, MRI and CT are able to provide structural details that are not achievable with PSFD - the detection sensitivity of PSFD decreases during the resection process as the volume of non-resected disease diminishes - the sensitivity of fluorescence imaging is not affected 194. PSFD had its first widespread and successful implementation in identifying diseased tissue after Kennedy and Pottier introduced an alternative approach of enhanced endogenous protoporphyrin (PPIX) production in the haem cycle of tumours in the early 1990s 231, 232. The strategy is based on the in situ conversion of ALA, a non-photoactivatable precursor, into PPIX, a naturally occurring photosensitising species via the cellular haem biosynthesis pathway (Figure S1/scheme 1). In the synthetic pathway iron is inserted into the PPIX cavity to form haem; the ferrochelatase enzyme that catalyses this chelation is down-regulated in many tumours and as a result iron is chelated into the PPIX cavity at a relatively low rate and is unable to compensate for the excess PPIX formed - significant accumulation of PPIX in neoplastic tissue occurs as a result following administration of exogenous ALA. The rates of ALA uptake in healthy verses neoplastic tissue are thought to be comparable; it is the differential rates of ALA conversion and resulting accumulation of PPIX that are the primary force behind favourable tumour selectivity 194, 233. PSFD has proved a powerful tool in the detection and guided resection of bladder cancer and has been reviewed by Witjes and Douglass 194, 234. Bladder cancer is the fourth most common malignancy in men and the industrial world; it has a high rate of recurrence and is a very costly cancer to treat and monitor 235-237. A critical factor in predicting disease recurrence is the detection of carcinomas in situ (CIS); these flat lesions are particularly difficult to detect with white light due to the poor contrast they generate 194, 236. Levulan® has proved successful in the fluorescence identification of numerous bladder lesions that were not detected by white light bronchoscopy; the detections were 100% supported by histological validation 194, 238-241. In the follow-up assessment of patients with fluorescence imaging, the superior sensitivity of the modality led to a reduced rate of early recurrence of superficial bladder cancer in comparison to white light evaluation 242. In a phase III trial, comparing transurethral guided resection using ALA verses white light cystoscopy, 61.5% of the patients in the PPIX fluorescence endoscopy group were tumour-free at the follow-up assessment in comparison to only 40.6% in the white light group 243. The hexylester derivative of ALA, Hexvix®, has been used to achieve greater tissue penetration depths into the urothelial layers and a more homogeneous distribution in malignant tissue; Hexvix® produced a stronger fluorescence intensity at a lower dose following a shorter incubation time 244. Fluorescence-guided resection (FGR) has also been used in the treatment of brain cancer; when ALA-induced PPIX was used in a guided resection study 63% of the patients achieved complete resection through contrast enhancement. A phase III trial was terminated at the interim analysis of 270 patients, when 65% of those in the FGR group (procedure followed by standard adjuvant radiotherapy) were free of residual disease at the post-operative 6 month assessment (by MRI), compared with 36% in the white light group. It is noted that the survival curves for the patients in both groups converged after 15 months 194, 245. Foscan®, particularly suited to imaging and treating bulky brain tumours due to its depth of light penetration, has been evaluated by Zimmermann and colleagues for the FGR of malignant gliomas; in 138 tissue specimens from 22 of the patients, a sensitivity and specificity of 87.9% and 95.7% were achieved 194, 246. In 10 of the 22 patients, malignancies were not identified by white light examination but were exclusively identified by PSFD 194, 246. Foscan® has exhibited further advantages over ALA-induced PPIX in that after several minutes of illumination it does not undergo photobleaching. To date, FGR has been invaluable in improving the extent to which tumour tissue can be removed but is now beginning to show promise in cases where a tumour cannot be completely removed because it has infiltrated functional brain tissue; the residual tumour tissue can be treated with pdt. In a standard treatment protocol, surgical resection is followed by adjuvant radiotherapy, however, when FGR is used instead of white light, the photosensitiser is already present in the tissue at the time of resection; a logical extension of the procedure would be to use pdt to selectively destroy any residual disease in the resection bed - a great example demonstrating the promise of theranostic regimens. Kostron and colleagues reported results from a study on FGR with adjuvant pdt in a group of patients (26) with malignant brain tumours using m-THPC; an increase in median survival from 3½ months to 9 months was achieved 247.

Bottom Line: Porphyrinic molecules have a unique theranostic role in disease therapy; they have been used to image, detect and treat different forms of diseased tissue including age-related macular degeneration and a number of different cancer types.Current focus is on the clinical imaging of tumour tissue; targeted delivery of photosensitisers and the potential of photosensitisers in multimodal biomedical theranostic nanoplatforms.The roles of porphyrinic molecules in imaging and pdt, along with research into improving their selective uptake in diseased tissue and their utility in theranostic applications are highlighted in this Review.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, The University Of Hull, Kingston-Upon-Hull, HU6 7RX, U.K.

ABSTRACT
Porphyrinic molecules have a unique theranostic role in disease therapy; they have been used to image, detect and treat different forms of diseased tissue including age-related macular degeneration and a number of different cancer types. Current focus is on the clinical imaging of tumour tissue; targeted delivery of photosensitisers and the potential of photosensitisers in multimodal biomedical theranostic nanoplatforms. The roles of porphyrinic molecules in imaging and pdt, along with research into improving their selective uptake in diseased tissue and their utility in theranostic applications are highlighted in this Review.

No MeSH data available.


Related in: MedlinePlus