Special Issue Review Received 25 June 2013,
Accepted 29 October 2013
Published online 19 December 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3166
Radiolabelled porphyrins in nuclear medicine† Philip A. Waghorna,b* Amongst tumour-specific substances, hematoporphyrin and synthetic porphyrin derivatives have been widely investigated to identify and delineate neoplastic and malignant tissue. Whilst the tumour localization exhibited by selected porphyrin species has been exploited through photodynamic therapy, several examples of porphyrin derivatives with varied peripheral functionality have been radiolabelled with the aim of developing porphyrin-based nuclear imaging and therapeutic agents. In this review, we look at the approaches and advances in the preparation and uses of such radiolabelled agents for imaging and therapy. Keywords: porphyrins; PET; SPECT; imaging; fluorescence; therapy
Introduction Porphyrins offer excellent potential and scope as imaging agents as they are potent fluorophores, they are biologically compatible, their metal complexes are both thermodynamically and kinetically stable and they exhibit high intrinsic specificity for tumours, both with and without the presence of a coordinated metal in the central core.1,2 Whilst porphyrin agents are site nonspecific drugs,3 their avidity for tumour tissue correlates strongly with the interplay between their lipophilicity and water solubility. On entering the bloodstream, they become associated with circulating proteins including low-density lipoproteins and glycoproteins.4 Cancer cells that undergo rapid growth require an increased supply of these proteins, and as such, their uptake is up-regulated. Protein bound porphyrins may also leak into the interstitium and become retained by the enhanced permeability and retention effect, as a result of the increased vascular permeability of tumour vessels and poorly developed lymph tissue. Low interstitial pH and large interstitial spaces with high amounts of collagen have also been shown to favour accumulation of porphyrins into tumour tissue.5–7 The work of Nakajima et al. established that porphyrins can also bind to human serum albumin and transferrin,8 with transferrin receptors elevated in cancer tissue in similar fashion to low-density lipoprotein. Such tumour selectivity has led to widespread development of porphyrins as agents for photodynamic therapy (PDT),9–11 chemotherapy,12 boron neutron capture therapy13–15 and in magnetic resonance imaging.16–18
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Though the emphasis has been on their therapeutic effects, based on their specific localization and sensitizing ability, porphyrins have the potential for use in tumour imaging and biodistribution studies through radiolabelling.19,20 Quenching of the fluorescence of the hematoporphyrin species (Figure 1A) by body fluids, blood and normal tissue and the limited penetration depth of visible and near infrared light into tissue has restricted the development of fluorescence imaging in combination with PDT, and as such, radiolabelled porphyrins
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provide an alternative non-invasive method for deep-tumour detection, and as a means to directly assess PDT treatment progression. Indeed, early work with 3H and 14C radiolabelling was used to observe the specific uptake in tumours by hematoporphyrin.21–23 Hematoporphyrin and its derivatives have been radiolabelled using 99mTc pertechnetate and stannous chloride, with radiolabelling believed to occur at the carboxylic chains of the porphyrin.24,25 The 99mTc-labelled species was shown to be stable under saline and serum challenges, and blood samples taken post injection (p.i.) showed that greater than 80% of the radiolabelled porphyrin species was still present intact after 24 h incubation. Localization was subsequently shown in mammary adenocarcinomas and in neoplasma by in vivo single-photon emission computed tomography imaging in tumour bearing rats. Hematoporphyrin labelled with 57Co and 64Cu coordinated in the tetrapyrrole core, was shown to lack significant tumour localization,26,27 however, whilst labelling with 109Pd was shown to accumulate in murine tumour models,28 poor tumour visualization in human models was later seen by the authors.29 Similarly with 111In, whilst the labelled species localized in murine breast tumours,30,31 substantial liver and spleen retention was again observed.32 High liver accumulation is common with all lipophilic porphyrin types, where the hepatobiliary excretion pathway is dominant. It has been shown that injection of hemin (protoporphyrin IX labelled
a CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK b Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
*Correspondence to: Philip A. Waghorn, CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK. E-mail: [email protected] †
This article is published in the Journal of Labelled Compounds and Radiopharmaceuticals as a special issue on ‘Current Developments in PET and SPECT Imaging’, edited by Jonathan R. Dilworth, University of Oxford and Sofia I. Pascu, University of Bath.
Copyright © 2013 John Wiley & Sons, Ltd.
P. A. Waghorn Biography Philip Waghorn was born in Tonbridge, UK, in 1984. He received his DPhil in Inorganic Chemistry in 2010 from the University of Oxford where he studied porphyrins as molecular imaging agents in the group of Professor Jon Dilworth. He then joined the group of Professor Kate Vallis as a postdoctoral research assistant at the Radiobiology Research Institute, University of Oxford. His current research focuses on the development of Auger-electron emitting therapeutic agents targeted against telomerase.
with iron chloride) into rats with an ovarian cancer model before injection of a series of 111In-labelled hematoporphyrin species led to increased plasma retentions times, increased tumour accumulation and decreased liver accumulation of the radiolabelled porphyrin species.33 More recently, Liu et al. have conjugated a tridentate histidine chelator to hematoporphyrin derivative and labelled with the 99mTc(I)(CO)3 core. Although the hematoporphyrin derivative was a mixture of three inseparable porphyrin species (protoporphyrin IX, HVD and hematoporphyrin), the total porphyrin radiochemical purity was > 99%. Biodistribution studies show tumour accumulation with tumour-to-blood (T/B) and tumour-to-muscle (T/M) ratios of 1.49 ± 0.19 and 5.27 ± 0.12, respectively, at 24 h p.i. Accumulation was similar to that of unlabelled hematoporphyrin in C6-glioma bearing mice.34
Tetraphenylporphyrin labelling As well as natural porphyrin analogues, a host of synthetic porphyrin species have been prepared as therapeutic PDT agents,3 warranting interest from a nuclear medicine perspective. Few
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Figure 1. Structures of (A) hematoporphyrin; (B) tetraphenylporphyrin and 5,10,15,20- tetrakis (4-sulfonatophenyl)porphyrin; (C) 5,10,15,20-tetrakis[3,4-bis (carboxymethyleneoxy)phenyl] porphyrin; and (D) sulfonated phthalocyanines.
examples of direct radiolabelling of tetraphenylporphyrin (TPP, Figure 1B) in its central core with 99mTc have been reported. Most recently attempts have included labelling TPP with an in situ prepared acetylacetone (acac) species of 99mTc in line with preparations for lanthanide and actinide labelled porphyrins.35 Though distinct from the 99mTc-pertechnetate and 99mTc(acac) starting materials, multiple unidentified products were observed by size exclusion chromatography. Further structural analysis and characterization will be required before these studies can be advanced into in vivo work.36 Direct labelling of TPP with 99 Tc2(CO)10 has been carried out in decalin under reflux conditions, yielding a series of labelled porphyrins of the formula [Tc(CO)3]n(porphyrin) (n = 1 or 2), which were structurally characterized and shown to have three porphyrin nitrogens bound to the technetium carbonyl fragment. Similar complexes with a non-radioactive rhenium isotope were also prepared.37,38 Recent preparations to directly label with the 99mTc tricarbonyl core have been attempted to produce kinetically stable 99mTc complexes of the water soluble 5,10,15,20- tetrakis(4-sulfonatophenyl)porphyrin (TPPS4, Figure 1B) ligand. The synthetic TPPS4 was previously labelled with 3H, 35S and 14C and studied in vivo. Whilst the 14Clabelled derivative was shown to possess favourable T/M ratios, the 3H and 35S-labelled compounds displayed only weak tumour uptake, attributable in the case of 35S as a result of sulfonate lability in vivo.39,40 Labelling of TPPS4 with 99mTc(I)(CO)3 was achieved with a 90% radiolabelling yield though the species formed has not been fully structurally characterized using either Re or 99Tc analogues. Disappointingly, the reported species showed an absence of uptake in both Hep2 tumour cells and in transplanted hepatoma tissue.41 The 57Co, 64Cu and 109Pd radiolabelled derivatives of TPPS4 also lacked tumour selectivity suggesting that these metallo-porphyrins lose all tumour affinity when their central tetrapyrrole core is occupied with these isotopes.29,42 Conversely, the rhenium(V) oxo derivative which was synthesized by heating the ligand with perrhenate and stannous tartrate as a reducing agent at 100°C was shown by Jia et al. to display favourable T/B ratios in melanoma and hepatoma studies with T/M ratios of 22.14 and 26.09, respectively.43 Whilst examples of direct radiolabelling with technetium or rhenium in the tetrapyrrole core are limited, several indirect labelling examples have been reported by appropriate functionalization of the periphery of the porphyrin structure. 99mTclabelled 5,10,15,20- tetrakis[3,4-bis(carboxymethyleneoxy)phenyl] porphyrin (TCPP, Figure 1C)44,45 and dendritic analogues46 have been shown by radio-HPLC to be stable in serum and saline over 48 h and to accumulate in glioma and breast tumour models. An analogous approach using cyclam to bind the 99mTc-oxo core gave T/M ratios of 6.93% in mammary tumour models and 5.58% in C6-glioma models. The T/M ratios for this agent in C6-glioma were superior to that of both 99mTc-citrate and 14C/3H-labelled hematoporphyrin, highlighting the potential of this complex as a tumour-localizing agent. The rhenium oxo complex of TCPP has been similarly prepared as a potential therapeutic analogue of the 99mTc agent by labelling with 186/188Re, though as with technetium species, the exact structure of the complex has not yet been rigorously established.47 Labelling with rhenium was achieved in 98% radiochemical yield, and in both fibrosarcoma and thymic lymphoma tumour models, high tumour retention was observed 24 h p.i., with extensive renal excretion and limited non-target organ uptake. Follow-up work with the pure 188Re-labelled species with fibrosarcoma tumours showed regression in tumour volume
P. A. Waghorn growth, when treated with two doses of 55 MBq of agent at 0 and 4 days, with a 33% tumour volume reduction after 8 days.48 Attempts to label TCPP with 109Pd reported the palladium bound to the tetrapyrrole core affording a highly stable chelated complex whilst the peripheral ester groups imparted optimized lipophilicity for high tumour accumulation and retention.49 Strong tumour uptake was observed with 5.28 ± 1.46% ID/g after 30 min p.i. with favourable T/B and T/M ratios observed (1.69 ± 0.23 and 5.00 ± 1.54, respectively 3 h p.i.), though very high liver accumulation was also seen (>20% ID/g).49 Attempts to prepare kinetically inert and structurally welldefined Tc(I) and Re(I) tricarbonyl species labelled at the porphyrin periphery have similarly been investigated.50 Spagnul et al. have recently prepared new, water soluble, charged porphyrins capable of binding 99mTc(I)(CO)3 via ethylenetriamine or bipyridyl ligands. Radiolabelling was achieved in quantitative yields with HPLC elution times in good agreement with their cold rhenium analogues. Such chelation options will be readily extended to alternative porphyrin units for future imaging and therapy strategies.51 As well as 99mTc, TPP has been radiolabelled with 111In in the tetrapyrrole core to give a complex which is stable to loss of 111 In in the presence of serum proteins.52 Further recent studies have been carried out, with other imaging and therapeutic radioisotopes including 64Cu, 68/67Ga, 140Nd and 166Ho.53–56 Whilst the analogous ‘cold’ complexes were not fully characterized, all species formed were shown to be stable to loss of radiometal under serum and saline challenges. Biodistribution studies on these various metal-labelled species showed minimal variation between metals with uptake dominated by the porphyrin species. Exchange of TPP for the more polar 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin, labelled with 68Ga or 64Cu led to enhanced renal excretion.57,58 Similarly, early work by Robinson et al. involving the labelling of TPP derivatives with 111In and 67Ga incorporating sulfonate, pyridinium and anilinium functionality on the porphyrin periphery, modulated solubility and lipophilicity and subsequent porphyrin biodistribution and tumour selectivity.59–61 From a therapeutic perspective, 213Bi has recently been incorporated into TPP as an alternative chelator to DTPA and DOTA labelling. Whilst direct labelling of the TPP motif requires forcing conditions, functionalization of the TPP with at least one carboxylic acid group allows for chelation to the out-ofplane bound bismuth ion, achieving a complex that remained stable in cell culture media over 8 h. Whilst direct labelling at pH 7, 40°C for 10min gave a moderate radiolabelling yield of 35%, it was shown subsequently that transmetallation from the analogous Pb species led to a reaction half-time of less than 2 s. Such a transmetallation is thought to facilitate the 213Bi radiolabelling, where having undergone decay to its daughter isotope, 209Pb, the Pb isotope becomes chelated by the porphyrin instantaneously allowing for in situ transmetallation with the remaining parent 213Bi isotope. Similar results were observed with a bifunctional ligand allowing for the further possibility of targeted delivery.62
Bifunctional chelators
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The bifunctional chelator approach to nuclear imaging allows direct delivery of radioisotopes to selected cellular targets by means of a cancer specific biomolecule conjugated to a kinetically and thermodynamically stable chelator by means of
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a pharmacokinetic modulating linker. Porphyrins are ideal building blocks in the bifunctional chelator approach as they offer potential roles as either a metal isotope chelator or as a targeting vector. To this end, efforts have been made to prepare a 177Lu-labelled DOTA agent conjugated to a tumour targeting porphyrin for radiotherapy possibilities. Fibrosarcoma tumour accumulation in Swiss mice was found to be 1.59 ± 0.52% ID/g with a T/B ratio of 8.56 ± 0.50 and T/M ratio of 26.5 ± 4.36 at 48 h. Tumour growth was retarded in treated animals, leading to a 68% decrease in tumour size after 8 days, following an initial dose of 92.5 MBq.63,64 A structurally similar agent has been prepared with a Gd-labelled DOTA unit coupled to a porphyrin for potential multi-functional magnetic resonance imaging/positron emission tomography (PET) imaging,65 and deuteroporphyrin, was previously functionalized to accommodate 111In labelling using conventional chelating groups.66 Alternatively, Shi et al. have opted to use the porphyrin entity in a purely chelator role and prepared 64Cu-labelled pyropheophorbide-α (a near infrared fluorescent porphyrin) coupled to folic acid for enhanced folate receptor mediated uptake in cancer tissue (Figure 2A). The conjugate was stable in serum and saline and metabolic studies assessed by HPLC analysis of urine samples collected 1 h p.i. showed the agent to be fully intact. Tumour uptake in folate receptor positive KB xenograft mouse models was 3.02 ± 0.55% ID/g at 4 h and 1.64 ± 0.33% ID/g at 24 h with a T/M ratio of 8.88 ± 3.60 at 24 h. Scintigraphy studies were performed, showing clear delineation of folate expressing tumours with subsequent blocking studies indicating receptor mediated tumour uptake.67 In recent
HO
O O
O
N
NH
HN
H
H
OH
I
N H O
O MeO2C
N HN
O N C6H13
NH
HO Figure 2. Structures of radiolabelled analogues of pyropheophorbide-α (A–C) and purpurinimide (D).
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P. A. Waghorn follow-up work, Liu et al. have shown by both optical and PET imaging studies that the 64Cu-labelled pyropheophorbide-α-folic acid species localized in primary human serous ovarian cancer xenografts which overexpress the folate receptor. Accumulation was shown in bulk tumour (T/M ratios of 8.91 ± 0.91 and 7.94 ± 3.94 at 24 h p.i. by PET and fluorescence imaging, respectively) and in micro-metastatic studding in the peritoneum. Such detailed localization could allow for more complete tumour debulking as well as a means to map disease progression and recurrence post-treatment.68 Studies by Mukai et al. to evaluate targeted PDT agents have led to the preparation of 64Cu-labelled protoporphyrin IX (PPIX) coupled to bombesin for binding to gastrin-releasing peptide receptors (GRPR).69 Enhanced uptake in GRPR positive PC-3 human prostate cancer cells was observed for the bombesinporphyrin construct, but significant, non-specific, receptor independent uptake by the 64Cu-labelled PPIX alone was also observed. In comparison with the DOTA-labelled analogue, the increased porphyrin lipophilicity led to increased blood retention times in mice bearing PC-3 tumours resulting in high liver and kidney accumulation and poor tumour visualization. To similar ends, radiolabelled porphyrins have been functionalized with biologically relevant entities such as antibodies, antibody fragments, peptides and proteins. Chelators such as porphyrins that bind radiometals with high stability under physiological conditions are ideal for radioimmunoimaging where it is essential to ensure high-target specificity by minimizing transcomplexation of the radiometal over the extended in vivo accumulation times necessary for antibody targeting.70 Bedel-Cloutour et al. labelled several monoclonal Immunoglobulin G antibodies and fragment antigen binding species with indium-labelled tritoyl substituted porphyrins using activated esters.71 Up to 10 molecules of radiotracer were attached to the monoclonal antibodies and 1.5 for antibody fragments. Immunoreactivity of the antibodies was shown not to be altered by the presence of the porphyrin entity. Copper-labelled porphyrins have also been used as bifunctional chelators to achieve labelling of biomolecules.72 Copper porphyrins have shown improved kinetic stability with respect to loss of the metal ion to serum proteins, compared with conventional chelators.73,74 An anti-renal cell carcinoma antibody was labelled with 67Cu at ambient conditions through benzyl activation of the porphyrin unit. Uptake of the antibody conjugate was fourfold higher than with the radiolabelled porphyrin alone, though extensive localization was still also observed in the liver and spleen.75,76 Whilst antibodies labelled with 67Cu by Lavallee et al. have been noted to retain 80% of their immunohistochemical activity, those labelled with 64Cu only retained 60% of the original antibody activity. The high energy γ photon (1.35 MeV), the positron and its associated annihilation photons (0.511 MeV), and the electron capture process occurring during the decay of 64Cu have been suggested to be responsible for radiolytic damage to the antibody and the differences in immunohistochemical activity.73
Nonmetal-labelled porphyrins
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Efforts have been made to prepare fluorine-labelled porphyrins as potential tumour markers to augment the role of [18F]-FDG. Methods have included the acid catalysed condensation of pyrrole, anisaldehyde and 4-[18F]-fluorobenzaldehyde or by the acid catalysed condensation of tetrapyrrane with 4-[18F]-
fluorobenzaldehyde. Radiochemical yields of 12.7% and 22.8% respectively have been obtained after semi-preparative HPLC.77 No in vivo work however, has yet been carried out with an 18 F-labelled porphyrin species. Inclusion of highly aromatic groups such as naphthyl groups in the place of the porphyrin phenyl groups have been shown to increase tumour uptake; however, whilst attempts to radiolabel sulfonated and unsulfonated 5,10,15,20-tetrakis(2hydroxynaphthyl)porphyrin with 125I have been made, neither of the compounds were shown to have significant tumour uptake, with activity strongly associated with the liver and spleen.78 To increase the hydrophilicity of the porphyrin, Lee et al. introduced methylene carboxylic acid groups to give 5-(3-(3-[123I]iodoallyloxy)phenyl)-10,15,20-tris-(3-carboxymethoxyphenyl)porphyrin, with labelling achieved using the stannane precursor. Biodistribution studies showed a timedependent accumulation of porphyrin in tumour tissue with 10.35% ID/g at 6 h. The tracer was shown to have significant activity in the blood, liver, kidneys and spleen, but all organs except the liver were shown to have fast washout after 6 h p.i. Low thyroid retention was indicative of a stable iodo-radiolabelled porphyrin in vivo.79 Pandey et al. have 124I-labelled several derivatives of 3-(1’-mhexyloxyethyl)-3-devinyl pyropheophorbide-α (HPPH),80 a promising photosensitizing agent for PDT. The concept of dual fluorescence and PET imaging with concomitant PDT as multimodal imaging agents allows better consideration of the pharmacokinetic and pharmacodynamic characteristics of photosensitizers allowing improved agent development. The non-radioactive iodine analogue, methyl-3-devinyl-3-[1’(miodobenzyloxy)ethyl] pyropheophorbide-α (Figure 2B) was shown to retain its photosensitizing ability, demonstrating 100% tumour-free progression 60 days after PDT at a drug concentration of 1.5 μmols kg-1. In vivo imaging was possible for superficial tumours where whole body fluorescence reflectance images were obtained for the photosensitizer localized within the tumour. Whilst fluorescence imaging from deeper organs was not possible, imaging by PET however revealed significant tumour uptake of the porphyrin at 24, 48 and 72 h p.i., though high accumulation was observed in the liver, kidneys and spleen. Substitution of the methyl ester for the free carboxylic acid was shown to enhance both tumour cell uptake and photosensitizing ability. A comparison of in vivo uptake with the 124I-labelled variants however showed the biodistributions to be comparable, except for a lower spleen uptake with the free acid derivative.81 The positioning of the iodine label was also shown to have a strong effect on cell uptake and photosensitizing ability, though no radiolabelling comparisons have yet been made.81 The HPPH structure labelled with 99mTc via a bisaminoethanothiol (N2S2) chelating group was synthesized showing strong tumour uptake, though the long accumulation times required of photosensitizing agents were not compatible with the short half-life of the 99m Tc.82 Similar structures with indium have been prepared for potential 111In labelling and shown to have increased photosensitizing ability in vivo with reduced skin cytotoxicity.83 Derivatives of HPPH functionalized with glucose and β-galactose (Figure 2C) for improved tumour uptake were prepared, but despite their enhanced in vitro uptake and photosensitizing abilities, the high liver and spleen uptake of both carbohydrate derivatives meant tumour delineation by microPET was not possible.84 Purpurimides which are effective photosensitizing agents with long wavelength absorptions were similarly studied
P. A. Waghorn by 124I labelling (Figure 2D). Again, enhanced liver and spleen uptake compared with the HPPH species was observed with poor delineation of tumours by microPET studies.85
Phthalocyanines Structurally similar to porphyrins, phthalocyanines (Pc) are potent photosensitizing agents in their own right and have been labelled with PET isotopes for both tumour imaging studies86 and for drug development strategies in the assessment of new PDT agents. The degree of Pc sulfonation has a strong influence on the degree of complex aggregation and on drug biodistribution and its subsequent potential as a photosensitizer. Recent synthetic developments allowed van Lier et al. to prepare phthalocyanines with increasing degrees of sulfonation and radiolabel each under microwave-assisted conditions with 64Cu. The water soluble, tri- and tetra-sulfonated phthalocyanines [64Cu]CuPcSn (n = 3,4, Figure 1D) displayed rapid renal clearance, with EMT-6 tumour localization below detection limits. The disulfonated analogue (n = 2) had a similar excretion pathway, but uptake in tumour increased continuously providing sufficient contrast with surrounding tissue for delineation by PET imaging. The highest tumour-to-background ratios were found with an amphiphilic hexynyl chain functionalized derivative (Figure 1D).87,88
Nanoparticles In the desire to image and treat disease, nanoparticle platforms have found widespread use as drug delivery vehicles. To this end, Liu and MacDonald et al. have recently developed radiolabelled porphysomes, which avoid the necessity of functionalization of the nanoparticle surface with metal radioisotope chelators (Figure 3). The porphysome nanoparticle, formed of lipid functionalized porphyrin units, was labelled directly with 64Cu with a radiochemical purity of 98%, with 64 Cu-labelled porphyrins contributing to < 5% of the porphysome, leaving the nanoparticle size and photonic properties largely unaffected. Evaluation of the radiolabelled
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Figure 3. a) Structure of Cu-radiolabelled porphyrin lipid, b) microPET/CT 64 images of prostate bone metastases (white arrows) labelled with Cu-radiolabelled porphysome nanoparticles. Reprinted (adapted) with permission from T. W. Liu et al., Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and Micrometastases, ACS Nano, 2013, 7, 4221. Copyright 2013 American Chemical Society. This figure is available in colour online at wileyonlinelibrary.com/journal/jlcr
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porphysome as a molecular imaging marker was explored preliminarily in a prostate cancer model amenable to porphysome uptake by the enhanced permeability and retention route. The low renal excretion of the porphysome allowed clear delineation of an orthotopic prostate cancer by both PET and fluorescence imaging with tumour uptake of 6.83% ID/g 24 h p.i. and a tumour-to-gut ratio of 1.53 and T/M ratio of 12.7. The porphysome was also able to delineate the presence of prostate cancer bone metastases. Such constructs have the potential to be labelled with a host of radioisotopes for imaging and therapy potentials with facile substitution of the porphyrin building blocks for optimized metal isotope binding, and for the targeted delivery by functionalization of the nanoparticle surface.89,90
Conclusion The intrinsic tumour avidity of natural and synthetic porphyrin species has provided continued interest for over 50 years in the development of new nuclear imaging agents as both standalone tumour markers and in combination with PDT as multimodal agents. Whilst a range of porphyrin complexes have been studied with different radioisotopes, no radiolabelled porphyrin species have yet been approved for clinical applications. The passive nature of the tumour accumulation is strongly dependent on porphyrin structure and choice of radioisotope, with the balance between hydrophilicity and lipophilicity recognized as an important factor in tumour accumulation. Whilst T/B and T/M ratios show favourable contrast, high nontarget organ uptake in liver, spleen and kidneys has restricted imaging possibilities. Development of porphyrins with greater tumour specificity with a strong emphasis on full structural characterization will need to be addressed if nuclear imaging with porphyrin agents is to be advanced into a clinical setting.
Conflict of Interest The authors did not report any conflict of interest.
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Accepted 29 October 2013
Published online 19 December 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3166
Radiolabelled porphyrins in nuclear medicine† Philip A. Waghorna,b* Amongst tumour-specific substances, hematoporphyrin and synthetic porphyrin derivatives have been widely investigated to identify and delineate neoplastic and malignant tissue. Whilst the tumour localization exhibited by selected porphyrin species has been exploited through photodynamic therapy, several examples of porphyrin derivatives with varied peripheral functionality have been radiolabelled with the aim of developing porphyrin-based nuclear imaging and therapeutic agents. In this review, we look at the approaches and advances in the preparation and uses of such radiolabelled agents for imaging and therapy. Keywords: porphyrins; PET; SPECT; imaging; fluorescence; therapy
Introduction Porphyrins offer excellent potential and scope as imaging agents as they are potent fluorophores, they are biologically compatible, their metal complexes are both thermodynamically and kinetically stable and they exhibit high intrinsic specificity for tumours, both with and without the presence of a coordinated metal in the central core.1,2 Whilst porphyrin agents are site nonspecific drugs,3 their avidity for tumour tissue correlates strongly with the interplay between their lipophilicity and water solubility. On entering the bloodstream, they become associated with circulating proteins including low-density lipoproteins and glycoproteins.4 Cancer cells that undergo rapid growth require an increased supply of these proteins, and as such, their uptake is up-regulated. Protein bound porphyrins may also leak into the interstitium and become retained by the enhanced permeability and retention effect, as a result of the increased vascular permeability of tumour vessels and poorly developed lymph tissue. Low interstitial pH and large interstitial spaces with high amounts of collagen have also been shown to favour accumulation of porphyrins into tumour tissue.5–7 The work of Nakajima et al. established that porphyrins can also bind to human serum albumin and transferrin,8 with transferrin receptors elevated in cancer tissue in similar fashion to low-density lipoprotein. Such tumour selectivity has led to widespread development of porphyrins as agents for photodynamic therapy (PDT),9–11 chemotherapy,12 boron neutron capture therapy13–15 and in magnetic resonance imaging.16–18
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Though the emphasis has been on their therapeutic effects, based on their specific localization and sensitizing ability, porphyrins have the potential for use in tumour imaging and biodistribution studies through radiolabelling.19,20 Quenching of the fluorescence of the hematoporphyrin species (Figure 1A) by body fluids, blood and normal tissue and the limited penetration depth of visible and near infrared light into tissue has restricted the development of fluorescence imaging in combination with PDT, and as such, radiolabelled porphyrins
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provide an alternative non-invasive method for deep-tumour detection, and as a means to directly assess PDT treatment progression. Indeed, early work with 3H and 14C radiolabelling was used to observe the specific uptake in tumours by hematoporphyrin.21–23 Hematoporphyrin and its derivatives have been radiolabelled using 99mTc pertechnetate and stannous chloride, with radiolabelling believed to occur at the carboxylic chains of the porphyrin.24,25 The 99mTc-labelled species was shown to be stable under saline and serum challenges, and blood samples taken post injection (p.i.) showed that greater than 80% of the radiolabelled porphyrin species was still present intact after 24 h incubation. Localization was subsequently shown in mammary adenocarcinomas and in neoplasma by in vivo single-photon emission computed tomography imaging in tumour bearing rats. Hematoporphyrin labelled with 57Co and 64Cu coordinated in the tetrapyrrole core, was shown to lack significant tumour localization,26,27 however, whilst labelling with 109Pd was shown to accumulate in murine tumour models,28 poor tumour visualization in human models was later seen by the authors.29 Similarly with 111In, whilst the labelled species localized in murine breast tumours,30,31 substantial liver and spleen retention was again observed.32 High liver accumulation is common with all lipophilic porphyrin types, where the hepatobiliary excretion pathway is dominant. It has been shown that injection of hemin (protoporphyrin IX labelled
a CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK b Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
*Correspondence to: Philip A. Waghorn, CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7LE, UK. E-mail: [email protected] †
This article is published in the Journal of Labelled Compounds and Radiopharmaceuticals as a special issue on ‘Current Developments in PET and SPECT Imaging’, edited by Jonathan R. Dilworth, University of Oxford and Sofia I. Pascu, University of Bath.
Copyright © 2013 John Wiley & Sons, Ltd.
P. A. Waghorn Biography Philip Waghorn was born in Tonbridge, UK, in 1984. He received his DPhil in Inorganic Chemistry in 2010 from the University of Oxford where he studied porphyrins as molecular imaging agents in the group of Professor Jon Dilworth. He then joined the group of Professor Kate Vallis as a postdoctoral research assistant at the Radiobiology Research Institute, University of Oxford. His current research focuses on the development of Auger-electron emitting therapeutic agents targeted against telomerase.
with iron chloride) into rats with an ovarian cancer model before injection of a series of 111In-labelled hematoporphyrin species led to increased plasma retentions times, increased tumour accumulation and decreased liver accumulation of the radiolabelled porphyrin species.33 More recently, Liu et al. have conjugated a tridentate histidine chelator to hematoporphyrin derivative and labelled with the 99mTc(I)(CO)3 core. Although the hematoporphyrin derivative was a mixture of three inseparable porphyrin species (protoporphyrin IX, HVD and hematoporphyrin), the total porphyrin radiochemical purity was > 99%. Biodistribution studies show tumour accumulation with tumour-to-blood (T/B) and tumour-to-muscle (T/M) ratios of 1.49 ± 0.19 and 5.27 ± 0.12, respectively, at 24 h p.i. Accumulation was similar to that of unlabelled hematoporphyrin in C6-glioma bearing mice.34
Tetraphenylporphyrin labelling As well as natural porphyrin analogues, a host of synthetic porphyrin species have been prepared as therapeutic PDT agents,3 warranting interest from a nuclear medicine perspective. Few
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Figure 1. Structures of (A) hematoporphyrin; (B) tetraphenylporphyrin and 5,10,15,20- tetrakis (4-sulfonatophenyl)porphyrin; (C) 5,10,15,20-tetrakis[3,4-bis (carboxymethyleneoxy)phenyl] porphyrin; and (D) sulfonated phthalocyanines.
examples of direct radiolabelling of tetraphenylporphyrin (TPP, Figure 1B) in its central core with 99mTc have been reported. Most recently attempts have included labelling TPP with an in situ prepared acetylacetone (acac) species of 99mTc in line with preparations for lanthanide and actinide labelled porphyrins.35 Though distinct from the 99mTc-pertechnetate and 99mTc(acac) starting materials, multiple unidentified products were observed by size exclusion chromatography. Further structural analysis and characterization will be required before these studies can be advanced into in vivo work.36 Direct labelling of TPP with 99 Tc2(CO)10 has been carried out in decalin under reflux conditions, yielding a series of labelled porphyrins of the formula [Tc(CO)3]n(porphyrin) (n = 1 or 2), which were structurally characterized and shown to have three porphyrin nitrogens bound to the technetium carbonyl fragment. Similar complexes with a non-radioactive rhenium isotope were also prepared.37,38 Recent preparations to directly label with the 99mTc tricarbonyl core have been attempted to produce kinetically stable 99mTc complexes of the water soluble 5,10,15,20- tetrakis(4-sulfonatophenyl)porphyrin (TPPS4, Figure 1B) ligand. The synthetic TPPS4 was previously labelled with 3H, 35S and 14C and studied in vivo. Whilst the 14Clabelled derivative was shown to possess favourable T/M ratios, the 3H and 35S-labelled compounds displayed only weak tumour uptake, attributable in the case of 35S as a result of sulfonate lability in vivo.39,40 Labelling of TPPS4 with 99mTc(I)(CO)3 was achieved with a 90% radiolabelling yield though the species formed has not been fully structurally characterized using either Re or 99Tc analogues. Disappointingly, the reported species showed an absence of uptake in both Hep2 tumour cells and in transplanted hepatoma tissue.41 The 57Co, 64Cu and 109Pd radiolabelled derivatives of TPPS4 also lacked tumour selectivity suggesting that these metallo-porphyrins lose all tumour affinity when their central tetrapyrrole core is occupied with these isotopes.29,42 Conversely, the rhenium(V) oxo derivative which was synthesized by heating the ligand with perrhenate and stannous tartrate as a reducing agent at 100°C was shown by Jia et al. to display favourable T/B ratios in melanoma and hepatoma studies with T/M ratios of 22.14 and 26.09, respectively.43 Whilst examples of direct radiolabelling with technetium or rhenium in the tetrapyrrole core are limited, several indirect labelling examples have been reported by appropriate functionalization of the periphery of the porphyrin structure. 99mTclabelled 5,10,15,20- tetrakis[3,4-bis(carboxymethyleneoxy)phenyl] porphyrin (TCPP, Figure 1C)44,45 and dendritic analogues46 have been shown by radio-HPLC to be stable in serum and saline over 48 h and to accumulate in glioma and breast tumour models. An analogous approach using cyclam to bind the 99mTc-oxo core gave T/M ratios of 6.93% in mammary tumour models and 5.58% in C6-glioma models. The T/M ratios for this agent in C6-glioma were superior to that of both 99mTc-citrate and 14C/3H-labelled hematoporphyrin, highlighting the potential of this complex as a tumour-localizing agent. The rhenium oxo complex of TCPP has been similarly prepared as a potential therapeutic analogue of the 99mTc agent by labelling with 186/188Re, though as with technetium species, the exact structure of the complex has not yet been rigorously established.47 Labelling with rhenium was achieved in 98% radiochemical yield, and in both fibrosarcoma and thymic lymphoma tumour models, high tumour retention was observed 24 h p.i., with extensive renal excretion and limited non-target organ uptake. Follow-up work with the pure 188Re-labelled species with fibrosarcoma tumours showed regression in tumour volume
P. A. Waghorn growth, when treated with two doses of 55 MBq of agent at 0 and 4 days, with a 33% tumour volume reduction after 8 days.48 Attempts to label TCPP with 109Pd reported the palladium bound to the tetrapyrrole core affording a highly stable chelated complex whilst the peripheral ester groups imparted optimized lipophilicity for high tumour accumulation and retention.49 Strong tumour uptake was observed with 5.28 ± 1.46% ID/g after 30 min p.i. with favourable T/B and T/M ratios observed (1.69 ± 0.23 and 5.00 ± 1.54, respectively 3 h p.i.), though very high liver accumulation was also seen (>20% ID/g).49 Attempts to prepare kinetically inert and structurally welldefined Tc(I) and Re(I) tricarbonyl species labelled at the porphyrin periphery have similarly been investigated.50 Spagnul et al. have recently prepared new, water soluble, charged porphyrins capable of binding 99mTc(I)(CO)3 via ethylenetriamine or bipyridyl ligands. Radiolabelling was achieved in quantitative yields with HPLC elution times in good agreement with their cold rhenium analogues. Such chelation options will be readily extended to alternative porphyrin units for future imaging and therapy strategies.51 As well as 99mTc, TPP has been radiolabelled with 111In in the tetrapyrrole core to give a complex which is stable to loss of 111 In in the presence of serum proteins.52 Further recent studies have been carried out, with other imaging and therapeutic radioisotopes including 64Cu, 68/67Ga, 140Nd and 166Ho.53–56 Whilst the analogous ‘cold’ complexes were not fully characterized, all species formed were shown to be stable to loss of radiometal under serum and saline challenges. Biodistribution studies on these various metal-labelled species showed minimal variation between metals with uptake dominated by the porphyrin species. Exchange of TPP for the more polar 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin, labelled with 68Ga or 64Cu led to enhanced renal excretion.57,58 Similarly, early work by Robinson et al. involving the labelling of TPP derivatives with 111In and 67Ga incorporating sulfonate, pyridinium and anilinium functionality on the porphyrin periphery, modulated solubility and lipophilicity and subsequent porphyrin biodistribution and tumour selectivity.59–61 From a therapeutic perspective, 213Bi has recently been incorporated into TPP as an alternative chelator to DTPA and DOTA labelling. Whilst direct labelling of the TPP motif requires forcing conditions, functionalization of the TPP with at least one carboxylic acid group allows for chelation to the out-ofplane bound bismuth ion, achieving a complex that remained stable in cell culture media over 8 h. Whilst direct labelling at pH 7, 40°C for 10min gave a moderate radiolabelling yield of 35%, it was shown subsequently that transmetallation from the analogous Pb species led to a reaction half-time of less than 2 s. Such a transmetallation is thought to facilitate the 213Bi radiolabelling, where having undergone decay to its daughter isotope, 209Pb, the Pb isotope becomes chelated by the porphyrin instantaneously allowing for in situ transmetallation with the remaining parent 213Bi isotope. Similar results were observed with a bifunctional ligand allowing for the further possibility of targeted delivery.62
Bifunctional chelators
B
A
N
124I
O
N
64Cu
N
N
H
NH
H O
H
N
N HN
O H
GDEVDGSGK-Folic Acid
O MeO2C
124I
C
124
D
O
NH N
H
HO
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The bifunctional chelator approach to nuclear imaging allows direct delivery of radioisotopes to selected cellular targets by means of a cancer specific biomolecule conjugated to a kinetically and thermodynamically stable chelator by means of
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a pharmacokinetic modulating linker. Porphyrins are ideal building blocks in the bifunctional chelator approach as they offer potential roles as either a metal isotope chelator or as a targeting vector. To this end, efforts have been made to prepare a 177Lu-labelled DOTA agent conjugated to a tumour targeting porphyrin for radiotherapy possibilities. Fibrosarcoma tumour accumulation in Swiss mice was found to be 1.59 ± 0.52% ID/g with a T/B ratio of 8.56 ± 0.50 and T/M ratio of 26.5 ± 4.36 at 48 h. Tumour growth was retarded in treated animals, leading to a 68% decrease in tumour size after 8 days, following an initial dose of 92.5 MBq.63,64 A structurally similar agent has been prepared with a Gd-labelled DOTA unit coupled to a porphyrin for potential multi-functional magnetic resonance imaging/positron emission tomography (PET) imaging,65 and deuteroporphyrin, was previously functionalized to accommodate 111In labelling using conventional chelating groups.66 Alternatively, Shi et al. have opted to use the porphyrin entity in a purely chelator role and prepared 64Cu-labelled pyropheophorbide-α (a near infrared fluorescent porphyrin) coupled to folic acid for enhanced folate receptor mediated uptake in cancer tissue (Figure 2A). The conjugate was stable in serum and saline and metabolic studies assessed by HPLC analysis of urine samples collected 1 h p.i. showed the agent to be fully intact. Tumour uptake in folate receptor positive KB xenograft mouse models was 3.02 ± 0.55% ID/g at 4 h and 1.64 ± 0.33% ID/g at 24 h with a T/M ratio of 8.88 ± 3.60 at 24 h. Scintigraphy studies were performed, showing clear delineation of folate expressing tumours with subsequent blocking studies indicating receptor mediated tumour uptake.67 In recent
HO
O O
O
N
NH
HN
H
H
OH
I
N H O
O MeO2C
N HN
O N C6H13
NH
HO Figure 2. Structures of radiolabelled analogues of pyropheophorbide-α (A–C) and purpurinimide (D).
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P. A. Waghorn follow-up work, Liu et al. have shown by both optical and PET imaging studies that the 64Cu-labelled pyropheophorbide-α-folic acid species localized in primary human serous ovarian cancer xenografts which overexpress the folate receptor. Accumulation was shown in bulk tumour (T/M ratios of 8.91 ± 0.91 and 7.94 ± 3.94 at 24 h p.i. by PET and fluorescence imaging, respectively) and in micro-metastatic studding in the peritoneum. Such detailed localization could allow for more complete tumour debulking as well as a means to map disease progression and recurrence post-treatment.68 Studies by Mukai et al. to evaluate targeted PDT agents have led to the preparation of 64Cu-labelled protoporphyrin IX (PPIX) coupled to bombesin for binding to gastrin-releasing peptide receptors (GRPR).69 Enhanced uptake in GRPR positive PC-3 human prostate cancer cells was observed for the bombesinporphyrin construct, but significant, non-specific, receptor independent uptake by the 64Cu-labelled PPIX alone was also observed. In comparison with the DOTA-labelled analogue, the increased porphyrin lipophilicity led to increased blood retention times in mice bearing PC-3 tumours resulting in high liver and kidney accumulation and poor tumour visualization. To similar ends, radiolabelled porphyrins have been functionalized with biologically relevant entities such as antibodies, antibody fragments, peptides and proteins. Chelators such as porphyrins that bind radiometals with high stability under physiological conditions are ideal for radioimmunoimaging where it is essential to ensure high-target specificity by minimizing transcomplexation of the radiometal over the extended in vivo accumulation times necessary for antibody targeting.70 Bedel-Cloutour et al. labelled several monoclonal Immunoglobulin G antibodies and fragment antigen binding species with indium-labelled tritoyl substituted porphyrins using activated esters.71 Up to 10 molecules of radiotracer were attached to the monoclonal antibodies and 1.5 for antibody fragments. Immunoreactivity of the antibodies was shown not to be altered by the presence of the porphyrin entity. Copper-labelled porphyrins have also been used as bifunctional chelators to achieve labelling of biomolecules.72 Copper porphyrins have shown improved kinetic stability with respect to loss of the metal ion to serum proteins, compared with conventional chelators.73,74 An anti-renal cell carcinoma antibody was labelled with 67Cu at ambient conditions through benzyl activation of the porphyrin unit. Uptake of the antibody conjugate was fourfold higher than with the radiolabelled porphyrin alone, though extensive localization was still also observed in the liver and spleen.75,76 Whilst antibodies labelled with 67Cu by Lavallee et al. have been noted to retain 80% of their immunohistochemical activity, those labelled with 64Cu only retained 60% of the original antibody activity. The high energy γ photon (1.35 MeV), the positron and its associated annihilation photons (0.511 MeV), and the electron capture process occurring during the decay of 64Cu have been suggested to be responsible for radiolytic damage to the antibody and the differences in immunohistochemical activity.73
Nonmetal-labelled porphyrins
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Efforts have been made to prepare fluorine-labelled porphyrins as potential tumour markers to augment the role of [18F]-FDG. Methods have included the acid catalysed condensation of pyrrole, anisaldehyde and 4-[18F]-fluorobenzaldehyde or by the acid catalysed condensation of tetrapyrrane with 4-[18F]-
fluorobenzaldehyde. Radiochemical yields of 12.7% and 22.8% respectively have been obtained after semi-preparative HPLC.77 No in vivo work however, has yet been carried out with an 18 F-labelled porphyrin species. Inclusion of highly aromatic groups such as naphthyl groups in the place of the porphyrin phenyl groups have been shown to increase tumour uptake; however, whilst attempts to radiolabel sulfonated and unsulfonated 5,10,15,20-tetrakis(2hydroxynaphthyl)porphyrin with 125I have been made, neither of the compounds were shown to have significant tumour uptake, with activity strongly associated with the liver and spleen.78 To increase the hydrophilicity of the porphyrin, Lee et al. introduced methylene carboxylic acid groups to give 5-(3-(3-[123I]iodoallyloxy)phenyl)-10,15,20-tris-(3-carboxymethoxyphenyl)porphyrin, with labelling achieved using the stannane precursor. Biodistribution studies showed a timedependent accumulation of porphyrin in tumour tissue with 10.35% ID/g at 6 h. The tracer was shown to have significant activity in the blood, liver, kidneys and spleen, but all organs except the liver were shown to have fast washout after 6 h p.i. Low thyroid retention was indicative of a stable iodo-radiolabelled porphyrin in vivo.79 Pandey et al. have 124I-labelled several derivatives of 3-(1’-mhexyloxyethyl)-3-devinyl pyropheophorbide-α (HPPH),80 a promising photosensitizing agent for PDT. The concept of dual fluorescence and PET imaging with concomitant PDT as multimodal imaging agents allows better consideration of the pharmacokinetic and pharmacodynamic characteristics of photosensitizers allowing improved agent development. The non-radioactive iodine analogue, methyl-3-devinyl-3-[1’(miodobenzyloxy)ethyl] pyropheophorbide-α (Figure 2B) was shown to retain its photosensitizing ability, demonstrating 100% tumour-free progression 60 days after PDT at a drug concentration of 1.5 μmols kg-1. In vivo imaging was possible for superficial tumours where whole body fluorescence reflectance images were obtained for the photosensitizer localized within the tumour. Whilst fluorescence imaging from deeper organs was not possible, imaging by PET however revealed significant tumour uptake of the porphyrin at 24, 48 and 72 h p.i., though high accumulation was observed in the liver, kidneys and spleen. Substitution of the methyl ester for the free carboxylic acid was shown to enhance both tumour cell uptake and photosensitizing ability. A comparison of in vivo uptake with the 124I-labelled variants however showed the biodistributions to be comparable, except for a lower spleen uptake with the free acid derivative.81 The positioning of the iodine label was also shown to have a strong effect on cell uptake and photosensitizing ability, though no radiolabelling comparisons have yet been made.81 The HPPH structure labelled with 99mTc via a bisaminoethanothiol (N2S2) chelating group was synthesized showing strong tumour uptake, though the long accumulation times required of photosensitizing agents were not compatible with the short half-life of the 99m Tc.82 Similar structures with indium have been prepared for potential 111In labelling and shown to have increased photosensitizing ability in vivo with reduced skin cytotoxicity.83 Derivatives of HPPH functionalized with glucose and β-galactose (Figure 2C) for improved tumour uptake were prepared, but despite their enhanced in vitro uptake and photosensitizing abilities, the high liver and spleen uptake of both carbohydrate derivatives meant tumour delineation by microPET was not possible.84 Purpurimides which are effective photosensitizing agents with long wavelength absorptions were similarly studied
P. A. Waghorn by 124I labelling (Figure 2D). Again, enhanced liver and spleen uptake compared with the HPPH species was observed with poor delineation of tumours by microPET studies.85
Phthalocyanines Structurally similar to porphyrins, phthalocyanines (Pc) are potent photosensitizing agents in their own right and have been labelled with PET isotopes for both tumour imaging studies86 and for drug development strategies in the assessment of new PDT agents. The degree of Pc sulfonation has a strong influence on the degree of complex aggregation and on drug biodistribution and its subsequent potential as a photosensitizer. Recent synthetic developments allowed van Lier et al. to prepare phthalocyanines with increasing degrees of sulfonation and radiolabel each under microwave-assisted conditions with 64Cu. The water soluble, tri- and tetra-sulfonated phthalocyanines [64Cu]CuPcSn (n = 3,4, Figure 1D) displayed rapid renal clearance, with EMT-6 tumour localization below detection limits. The disulfonated analogue (n = 2) had a similar excretion pathway, but uptake in tumour increased continuously providing sufficient contrast with surrounding tissue for delineation by PET imaging. The highest tumour-to-background ratios were found with an amphiphilic hexynyl chain functionalized derivative (Figure 1D).87,88
Nanoparticles In the desire to image and treat disease, nanoparticle platforms have found widespread use as drug delivery vehicles. To this end, Liu and MacDonald et al. have recently developed radiolabelled porphysomes, which avoid the necessity of functionalization of the nanoparticle surface with metal radioisotope chelators (Figure 3). The porphysome nanoparticle, formed of lipid functionalized porphyrin units, was labelled directly with 64Cu with a radiochemical purity of 98%, with 64 Cu-labelled porphyrins contributing to < 5% of the porphysome, leaving the nanoparticle size and photonic properties largely unaffected. Evaluation of the radiolabelled
64
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Figure 3. a) Structure of Cu-radiolabelled porphyrin lipid, b) microPET/CT 64 images of prostate bone metastases (white arrows) labelled with Cu-radiolabelled porphysome nanoparticles. Reprinted (adapted) with permission from T. W. Liu et al., Inherently Multimodal Nanoparticle-Driven Tracking and Real-Time Delineation of Orthotopic Prostate Tumors and Micrometastases, ACS Nano, 2013, 7, 4221. Copyright 2013 American Chemical Society. This figure is available in colour online at wileyonlinelibrary.com/journal/jlcr
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porphysome as a molecular imaging marker was explored preliminarily in a prostate cancer model amenable to porphysome uptake by the enhanced permeability and retention route. The low renal excretion of the porphysome allowed clear delineation of an orthotopic prostate cancer by both PET and fluorescence imaging with tumour uptake of 6.83% ID/g 24 h p.i. and a tumour-to-gut ratio of 1.53 and T/M ratio of 12.7. The porphysome was also able to delineate the presence of prostate cancer bone metastases. Such constructs have the potential to be labelled with a host of radioisotopes for imaging and therapy potentials with facile substitution of the porphyrin building blocks for optimized metal isotope binding, and for the targeted delivery by functionalization of the nanoparticle surface.89,90
Conclusion The intrinsic tumour avidity of natural and synthetic porphyrin species has provided continued interest for over 50 years in the development of new nuclear imaging agents as both standalone tumour markers and in combination with PDT as multimodal agents. Whilst a range of porphyrin complexes have been studied with different radioisotopes, no radiolabelled porphyrin species have yet been approved for clinical applications. The passive nature of the tumour accumulation is strongly dependent on porphyrin structure and choice of radioisotope, with the balance between hydrophilicity and lipophilicity recognized as an important factor in tumour accumulation. Whilst T/B and T/M ratios show favourable contrast, high nontarget organ uptake in liver, spleen and kidneys has restricted imaging possibilities. Development of porphyrins with greater tumour specificity with a strong emphasis on full structural characterization will need to be addressed if nuclear imaging with porphyrin agents is to be advanced into a clinical setting.
Conflict of Interest The authors did not report any conflict of interest.
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