[Frontiers in Bioscience 14, 872-886, January 1, 2009]
Roland Haubner1, Clemens Decristoforo1
1Clinical Department of Nuclear Medicine, Medical University Innsbruck, Austria,Anichstrasse 35, A-6020 Innsbruck, Austria
TABLE OF CONTENTS
1. ABSTRACT
Imaging techniques allowing non-invasive monitoring of tumour angiogenesis have attracted great interest over the last years. The integrin alpha(v)beta3 is overexpressed during tumour spread and metastasis and therefore is an attractive target for monitoring angiogenetic processes. This review summarizes attempts to develop radiolabelled peptides based on the Arg-Gly-Asp (RGD) sequence and related peptidomimetics with high affinity and selectivity for the alpha(v)beta3 integrin for tumour targeting. Most developments were based on cyclic RGD peptides radiolabelled with 18F, 64Cu, 68Ga for PET, 99mTc for SPECT or 177Lu for therapeutic applications. To enable fast elimination from non target tissue and rapid excretion of the radiolabelled peptides pharmacokinetic modifiers such as sugar amino acids have been evaluated. Out of these developments (18F)Galacto-RGD has shown high tumour-to-background ratios preclinically and has been evaluated in a number of clinical studies, showing the possibility for non invasive imaging of alpha(v)beta3 in tumour patients. To improve targeting efficiency multimeric constructs were reported revealing improved targeting properties in preclinical models. These developments still have to be transferred into the clinical setting.
2. ANGIOGENESIS AND TUMOUR GROWTH
Angiogenesis is the process that results in the formation of new vessels by sprouting of existing vessels into avascular tissue. Angiogenesis is involved in numerous biological processes, such as embryogenesis, tissue remodelling, female reproductive cycle, and wound healing. However, also numerous disorders are characterized by an imbalance or up-regulation of the angiogenic process. Best known are rheumatoid arthritis (1), psoriasis (2), restenosis (3), diabetic retinopathy (4) and especially tumour growth (5). Thus, the field of angiogenesis research is one of the most rapidly growing biomedical disciplines. The interest in this research is based on the potential aimed at developing anti-angiogenesis drugs as novel therapeutics in particular for treatment of tumours.
Growth and metastasis of solid tumours depend on the formation of new blood vessels which originate from the existing vascular system. These blood vessels grow into the tumour and provide the necessary nutrients and growth factors for tumour progression. Moreover, the newly formed blood vessels allow tumour cells to disseminate and form metastases in distant organs. Normally, vascular homeostasis is regulated by a balance between angiogenic and antiangiogenic factors (6, 7). Tumour-induced angiogenesis is mainly sustained by the production and secretion of angiogenic factors originating from tumour and stroma cells. It is a multistep process characterized by the chemotactic and mitogenic response of endothelial cells to angiogenic growth factors, proteolytic degradation of extracellular matrix, and modulation of endothelial cell interaction with extracellular matrix proteins mediated by a variety of receptors including the integrins (8-10).
3. TARGETING INTEGRIN EXPRESSION IN TUMOURS
Integrins play a key role during migration of endothelial cells in the basement membrane . They are not only involved in endothelial cell adhesion, they are also important regulators of endothelial cell growth, survival and differentiation. One member of this class of receptors is the integrin alpha(v)beta3, which has been shown to play an essential role in the regulation of tumour growth, local invasiveness, and metastatic potential . Moreover, alpha(v)beta3 is also highly expressed on activated endothelial cells during angiogenesis . Based on several knock-out experiments there is evidence that alpha(v)beta3 and alpha(v)beta5 are rather anti-angiogenic or negative regulators of angiogenesis than pro-angiogenic . Inhibition of alpha(v)beta3-mediated cell-matrix interactions has been found to induce apoptosis of activated endothelial cells. However, alpha(v)beta3 antagonists can induce apoptosis not only of endothelial cells but also of alpha(v)beta3-positive tumour cells, resulting in a direct cytotoxic effect on these cells . Thus, the use of alpha(v)beta3 antagonists is currently being evaluated as a strategy for anticancer therapy . However, the aim of such a treatment is prevention of metastasis and disease stabilization rather than reduction of tumour mass during a relatively short period of therapy ("response rate"). Therefore conventional monitoring schemes do not fit for this kind of therapy and new biomarkers are needed for planning and monitoring of treatments targeting the alpha(v)beta3 integrin. Furthermore such techniques may also supply information about the angiogenic process in an individual patient.
One approach to monitor alpha(v)beta3 expression is based on nuclear medicine tracer techniques, which allow non-invasive determination of radioactive compounds in the nanomolar range. Additionally radiolabelling with therapeutic radionuclides of such biomarkers may allow targeted radionuclide therapy of tumours. This review focuses on radiolabelled RGD derivatives used for targeting tumours.
4. ALPHA(V)BETA3 ANTAGONISTS FOR RADIOLABELLING
Integrins are heterodimeric transmembrane glycoproteins consisting of an alpha- and a beta-subunit. It is found that several extracellular matrix proteins like vitronectin, fibrinogen and fibronectin interact via the amino acid sequence arginine-glycine-aspartic acid (RGD, amino acid single letter code) with the integrins . Based on these findings linear as well as cyclic peptides including the RGD-sequence have been introduced (for review see ). Kessler and co-workers developed the pentapetide cyclo(-Arg-Gly-Asp-dPhe-Val-) which showed high affinity and selectivity for alpha(v)beta3. This peptide is the most prominent lead structure for the development of radiotracers for the non-invasive determination of the alpha(v)beta3 expression . Based on this pentapeptide a great variety of tracers have been synthesized which are discussed later in detail.
Another peptide used as a lead structure is the disulfide-bridged undecapeptide RGD-4C ((Cys2-Cys10,Cys4-Cys8)H-Ala-Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys-Gly-OH). RGD-4C binds with high affinity (KD ~ 100 nM) to both, the integrin alpha(v)beta3 and alpha(v)beta5 . The derivative ((Cys1-Cys9,Cys3-Cys7)H-Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys-OH) was conjugated with HYNIC and labelled using 99mTc-technetium . However, in murine tumour models only marginal tumour uptake was found, which can be explained by the low association constant of this 99mTc-labelled RGD-4C derivative for alpha(v)beta3 (7 x 106 M-1). Thus, either the deletion of the terminal amino acids, the conjugation with HYNIC, and/or the labelling with 99mTc-technetium impairs the affinity resulting in a peptide that appears unsuitable for in-vivo imaging of alpha(v)beta3 expression.
NC-100717 is a peptide based on the sequence H-Lys-Cys-Arg-Gly-Asp-Cys-Phe-Cys-OH whereby Nalpha of Lys1 is bridged with Cys8 via a chloroacetyl moiety and Cys2-Cys6 via disulfide formation, the Nε is used for derivatisation for radiolabelling with 18F, 99mTc (NC100692), or other radiometals. Additionally, the C-terminus is derivatised with a PEG linker as biomodifier. These peptides showed in vitro affinity and binding to alpha(v)beta3 and alpha(v)beta5 in the nanomolar range (EA-Hy 926 membrane assay).
Another group has derivatised a peptidomimetic vitronectin receptor antagonist SH066 with the bifunctional chelator 1,4,7,10-tetraazacyclodoadecane-N,N',N'',N'''-tetraacetic acid (DOTA) to give TA138. TA138 and 89Y-TA138 retained antagonist properties and high affinity for integrin alpha(v)beta3 (IC50 = 12 and 18 nM, respectively), and good selectivity versus integrin alpha(IIb)beta3 (IC50 > 10,000 nM). 111In-TA138 demonstrated high tumour uptake in a mouse mammary adenocarcinoma model (9.39% ID/g at 2 hours p.i.) and low background activity with rapid blood clearance and renal excretion. Further structure activity studies and dimerisation strategies make this class of compounds an interesting alternative to peptides based on the RGD sequence.
Based on the guanidinobenzoyl hydrazino oxopentanoic acid scaffold (GBHO) another class of radioiodine- and 18F-labelled nonpeptidic alpha(v)beta3 antagonists has been synthesized. Compared with (125I)Gluco-RGD, (123I)GBHO-1 showed an approximately 3-fold lower activity accumulation in alpha(v)beta3-expressing tumours. However, due to the rapid renal and hepatic elimination of (123I)GBHO-1, tumour-to-background ratios are comparable with those obtained with (125I)Gluco-RGD. Gamma-camera images of mice bearing alpha(v)beta3-positive M21 melanomas and corresponding M21-L control tumours demonstrated receptor-specific binding of (123I)GBHO-1. Even higher tumour-to-background ratios can be found for the 4-(18F)fluorobenzoylated derivative (18F)GBHO-2 (5-(N'-(3-guanidinobenzoyl)-hydrazino)-3-(4-(18F)fluorobenzoyl)-amino-5-oxopentanoic acid . Initial in vivo studies in mice and rats indicate that (18F)GBHO-2 may be an alternative to the (18F)Galacto-RGD for the in vivo imaging of alpha(v)beta3-expression.
Dijkgraaf et al. compared 111In-labelled DOTA-E-c(RGDfK) with a DOTA-peptidomimetic and a DOTA-conjugated peptoid-peptide hybrid (DOTA-E-c(nRGDfK)) and found that the peptide and peptidomimetic had higher alpha(v)beta3 affinities and better tumour-targeting characteristics as compared with the hybrid. Anyway, so far radiolabelling approaches have been mainly focused on cyclic RGD peptides and derivatives thereof partly due to the fact that peptidomimetics often are specifically designed to achieve bioavailability after oral administration, which is no requirement for radiopharmaceutical approaches where intravenous application is preferred.
5. RADIOLABELLING STRATEGIES
5.1. Halogens
For the first evaluation and potential use with single photon emission tomography (SPECT) the radioiodinated RGD peptides 3-(*I)Iodo-DTyr4-cyclo(-Arg-Gly-Asp-DTyr-Val-) and 3-(*I)Iodo-Tyr5-cyclo(-Arg-Gly-Asp-DPhe-Tyr-) have been synthesized by direct electrophilic radioiodination of the corresponding tyrosine residues in the peptide sequence . Both compounds showed in vitro affinity and selectivity for the alpha(v)beta3 integrin comparable with the lead structure, and receptor specific accumulation in the tumour in vivo. However, the predominantly hepatobiliary elimination resulted in high activity concentration in liver and intestine.
Fluorine-18 is the most frequently used radionuclide in Positron emission tomography due to its favourable half life of 110 minutes. For 18F-labelling using 4-nitrophenyl-2-(18F)fluoropropionate as prosthetic group a carbohydrate derivatised analogue was developed . This prosthetic group allowed synthesis of (18F)Galacto-RGD with a maximum decay-corrected radiochemical yield of about 30% and radiochemical purity >98% with a total synthesis time of 200 min. Initial in vivo evaluation was carried out using the human melanoma M21 model. The M21 cell line is well characterized concerning alpha(v)beta3 expression. Another advantage is that from M21 cells, stable variants were selected that lack alpha(v) gene expression and thus, fail to express integrin alpha(v)beta3 (M21-L cells) . Using this model (18F)Galacto-RGD uptake in the tumour 120 min p.i. was 1.5% ID/g . Blocking experiments injecting 6 mg c(RGDfV) per kg mouse 10 min prior to tracer injection reduced tumour accumulation to approx. 35% of control indicating receptor specific accumulation. This is confirmed by biodistribution experiments as well as imaging studies with a small animal PET scanner using nude mice bearing the M21 or the M21-L tumour. Furthermore, imaging studies with mice bearing melanoma tumours with increasing amounts of alpha(v)beta3 positive cells (produced by mixing M21 and M21-L cells) showed that there is a correlation between integrin expression and tracer accumulation . Altogether these data demonstrated that non-invasive determination of alpha(v)beta3 expression and quantification with 18F-labelled RGD-peptides is possible.
However, synthesis of 18F-labeled peptides using activated esters is complex and time consuming sometimes requiring complicated protection strategies, therefore chemoselective 18F-labelling strategies based on oxime formation using 4-(18F)fluorobenzaldehyde have been introduced in recent years . This prosthetic group has also been used in combination with HYNIC-modified RGD-peptides . The resulting 4'-(18F)-fluorobenzylidenehydrazone-6-nicotinamide-c(RGDyK) showed high affinity for alpha(v)beta3 and accumulates specifically in ischemic hindlimb muscle of mice. Most recently, amino-oxy-functionalisation was also used to conjugate (18F)fluorosilyl-benzaldehyde to a RGD-peptide. However, further evaluation is needed to demonstrate the potential of this new prosthetic group (41).
Prante et al. used 3,4,6-tri-O-acetyl-2-deoxy-2-(18F)fluoroglucopyranosylphenylthiosulfonate (Ac3-(18F)FGlc-PTS) as a thiol-reactive glycosyl donor for 18F-glycosylation of peptides. This approach would allow both introduction of the radiolabel and a pharmacokinetic modifier in one synthesis step. Using for first evaluation cyclo(-Arg-Gly-Asp-dPhe-Cys) it was shown that this labelling strategy allows 18F-labelling of the corresponding peptide in high radiochemical yields. Moreover, the in vitro assays demonstrated that the alpha(v)beta3 binding affinity remained unaffected.
Another strategy introduced by Cai et al. used N-(2-(4-18F-fluorobenzamido)ethyl)maleimide (18F-FBEM) as a thiol-reactive synthon. With this technique 18F-labeling of a monomeric and dimeric thiolated RGD peptide at high specific activities and high radiochemical yields could be carried out. Moreover, an integrin-specific tumour uptake in subcutaneous U87MG glioma and orthotopic MDA-MB-435 breast cancer xenografts with favourable pharmacokinetics was shown. Radiolabelling strategies and RGD peptides used for this purpose are summarized in table 1.
5.2. Technetium
Technetium-99m is the radionuclide of choice for SPECT applications due to its wide availability based on generator production and its favourable decay characteristics with a gamma energy of 140 keV and 6 hr half life. A variety of bifunctional chelators are available for radiolabelling of small peptides. Recently, cyclo(-Arg-Gly-Asp-dTyr-Lys-) was derivatised with a variety of ligands including hydrazino nicotinic acid (HYNIC), a pyrazolyl-derivative, an isonitril-conjugate and a Cys-moiety allowing radiolabelling with different Technetium-cores including Tc(CO)3, Tc-nitrido, Tc-hydrazino and the so called Tc-3+1 approach . The compounds could be labelled with high specific activities in high radiochemical yields and showed high in vitro stability for all Tc-cores studied. However, plasma protein binding and lipophilicity varied considerably between different radiolabelled conjugates, resulting in significant differences concerning pharmacokinetic behaviour as well as tumour uptake (0.2-2.7%ID/g). Highest specific tumour uptake was found for HYNIC-cyclo(-Arg-Gly-Asp-dTyr-Lys-) with ethylenediamnin N,N`diacetic acid (EDDA) as coligand. Other coligands based on tricine showed higher values of protein binding or lower in vitro binding affinity . Tumour/background ratios of 99mTc-EDDA/HYNIC-RGD were comparable to (18F)Galacto-RGD indicating that this compound could be a promising candidate for imaging alpha(v)beta3 expression using SPECT. Other groups have used tricine /TPPTS as coligands for radiolabelling HYNIC-derivatised monomers, dimers and tetramers .
A promising compound based on a tridentate pyrazolyl derivative using (Tc(CO)3(H2O)3)+ for radiolabelling was recently reported . The resulting 99mTc-tricarbonyl labelled peptide showed high and specific tumour uptake and high in vivo stability, the higher lipophilicity compared to HYNIC derivatised peptides resulted in somewhat higher hepatobiliary excretion and liver uptake. Other developments of 99mTc-tricarbonyl labelling of RGD peptides are based on a 5-carboxylate-2,2'-bipyridine derivatisation or on a His-derivatised peptide resulting in a bidentate chelating system . Jung et al. have used a glucoseamin derivatised RGD peptide (glucosamino-Asp-cyclic(Arg-Gly-Asp-dPhe-Lys)) functionalized with an aminodiacetic acid for Tc-tricarbonyl labelling. This derivative had a high binding affinity to purified alpha(v)beta3 integrin (IC50 = 1.5 nM) and showed rapid blood clearance, with substantially lower liver uptake and higher tumour uptake compared with 125I-c(Arg-Gly-Asp-dTyr-Val) in mice. Therefore it may be an attractive alternative to radiohalogenated RGD peptides for angiogenesis-imaging research. Another 99mTc-labelling approach was based on the tetrapeptide sequence H-Asp-Lys-Cys-Lys-OH resulting in a triamidomonothiol chelating sequence . For (99mTc)DKCK-RGD gamma-camera images 4 h p.i. showed a clearly contrasting tumour, but also high activity concentration in the kidneys, which may be due to the lysine containing tetrapeptide used as chelating sequence.
NC100692 is a peptide containing a cyclic RGD sequence coupled to an ethylene glycol biomodifier at the C-terminal end of the peptide and a diamine dioxime chelate for 99mTc-labelling linked to the N-terminal end . It binds with high affinity in particular to the alpha(v)beta3 integrin as shown by in vitro binding assays and competitive radiolabelled ligand assays. The use of NC100692 in ischemic models shows high uptake in areas of neovascularisation with alpha(v)beta3 integrin overexpression , and binding of NC100692 has been confirmed to be localized on endothelial cells in the regions of angiogenesis . The approaches towards 99mTc labelled RGD peptides including labelling moieties and Tc-cores applied are summarized in table 2.
5.3. Other radiometals
Within recent years also other radiometals have gained increasing interest as radiolabels for small biomolecules such as peptides. These include 111In for SPECT, 90Y and 177Lu for therapeutic applications and 68Cu and 68Ga for PET. Van Hagen et al. synthesized a diethylentriamine-pentaacetic acid- (DTPA) conjugated RGD-peptide and demonstrated alpha(v)beta3 selective binding on blood vessels of human tumour tissue sections using receptor autoradiography and immunohistochemistry. DTPA-RGD-peptides have also been synthesized using a solid-phase system . The in vitro and in vivo assays of the 111In-labelled derivatives showed selective binding and accumulation using the alpha(v)beta3 positive Melanoma M21 model. The authors suggest that this approach may allow construction of DTPA-containing peptide libraries for high throughput screening. DTPA, however, is not the ligand of choice for radiolabelling trivalent metals, especially for PET and therapy applications.
A DOTA conjugated RGD-peptide (DOTA-RGDyK) was labelled with 64Cu-copper . This tracer showed lower tumour uptake and retention in a murine orthotopic human breast cancer model as compared with the radioiodinated cyclo(-Arg-Gly-Asp-dTyr-Lys-) and unfavourable activity retention in liver and kidneys. The activity concentration in the liver could be due to transfer of 64Cu from DOTA to superoxide dismutase and/or the persistent localization of the final metabolite 64Cu-DOTA-Lys-OH in this tissue. Tumour/blood and tumour/muscle ratios of approximately 7 and 8, respectively, allowed acquisition of clear tumour/background contrast images 1 h p.i. using a small animal scanner. However, highest activity concentration was found in liver, intestine and bladder indicating that further optimization of the tracer is needed.
Another DOTA-derivatised RGD peptide (cyclo(-Arg-Gly-Asp-dPhe-Lys(DOTA)), DOTA-RGDfK) was used by Decristoforo et al. for radiolabelling with 111In and 68Ga . Both radiolabelled peptides showed specific binding to alpha(v)beta3 integrin with comparable internalisation and tumour uptake values to (18F)Galacto-RGD in an alpha(v)beta3 positive melanoma M21 model. However, protein binding was considerably higher for (68Ga)DOTA-RGDfK resulting in higher background activity in vivo and lower tumour/background values as compared to (18F)Galacto-RGD.
Radiolabelling with 177Lu and 90Y was reported for studying the therapeutic potential of radiolabelled RGD peptides. Jansen et al. used an 90Y-labelled RGD dimer (DOTA-E-(c(RGDfK))2) to study the effect of dose fractionation in OVCAR-3 ovarian carcinoma mouse xenografts. However, they found that the therapeutic efficacy of the radiolabelled peptide was not significantly improved by dose fractionation.
Using 111In and 177Lu labelled DOTA-E-c(RGDfK) the same group studied the effect on intraperitoneally (i.p.) growing OVCAR-3 human ovarian carcinomas and found that intraperitoneal growth of the tumour could be significantly delayed by injecting 37 MBq 177Lu-labelled peptide i.p. indicating the therapeutic potential of radiolabelled RGD peptides. Radiometal labelled RGD peptides are summarized in table 3.
6. OPTIMIZING PHARMAKOKINETICS
Optimal tumour targeting of radiolabelled RGD peptides is achieved with tracers having a rapid uptake in the tumour and at the same time a rapid washout and excretion from non target tissues. In this respect hydrophilic properties are warranted, and a variation in charge may be applied to achieve rapid renal excretion and low retention in organs such as kidney or liver. Therefore pharmacokinetic properties have been varied using chemical modifications ("pharmacokinetic modifiers") whereby different approaches have been reported.
The glycosylation approach was first described by Haubner and co-worker and is based on the introduction of sugar amino acids (sugar derivatives with an amino and a carboxylate function) which allows straight forward integration into peptide chemistry. The sugar amino acids (SAA) were conjugated via the ε-amino function of the corresponding lysine in the pentapeptide sequence. In a murine tumour model the resulting (*I)Gluco-RGD and (18F)Galacto-RGD showed an initially increased activity concentration in blood, very similar kinetics in kidneys and more important, a clearly reduced activity concentration in liver and an increased activity uptake and retention in the tumour compared to the first generation, unmodified peptides.
Another strategy is to introduce hydrophilic D-amino acids to improve pharmacokinetics of peptide-based tracer . Therefore, peptides containing three D-serine or D-aspartic acids and a γ-amino butyric acid for 18F-labelling via prosthetic groups were coupled with the corresponding cyclic RGD-peptide. D-amino acids were used to improve the metabolic stability of the compounds. The peptides showed high alpha(v)beta3 selectivity in vitro and receptor specific accumulation in vivo. The tumour uptake in a murine melanoma model was lower as found with the glycosylated RGD-peptides. However, due to the rapid predominantly renal elimination of (18F)dAsp3-RGD tumour/background ratios calculated from small animal PET images were comparable with (18F)Galacto-RGD.
PEGylation, the technology of poly(ethlyene glycol) (PEG) conjugation, is known to improve many properties of peptides and proteins including plasma stability, immunogenicity and pharmacokinetics . In many cases it is used to prolong median circulation times and half lives of proteins and polypeptides by shifting the elimination pathway from renal to hepatobiliary excretion. Since renal filtration is dependant on both the molecular mass and the volume occupied, this effect strongly depends on the molecular weight of the PEG moiety. In a first study, Chen et al. attached a 2 kDa PEG moiety to the ε-amino function of cyclo(-Arg-Gly-Asp-dTyr-Lys-) and compared the 125I-labelled PEGylated derivative (125I-RGD-PEG) with the radioiodinated cyclo(-Arg-Gly-Asp-dTyr-Lys-) (125I-RGD). The PEGylated derivative showed a more rapid blood clearance, a decreased activity concentration in the kidneys and slightly increased activity retention in the tumour. However, tumour uptake for 125I-RGD was higher as found for 125I-RGD-PEG for all time points. Moreover, as explained above, increased activity retention in liver and intestine was found. In another study (18F)FB-RGD, a (18F)fluorobenzoyl labelled RGD peptide, and the PEGylated analogue (18F)FB-PEG-RGD (PEG, MW = 3.4 kDa) have been compared . Again activity retention of the PEGylated peptide in the tumour was improved compared with the lead structure. However, initial elimination from blood was slower and activity concentration in liver and kidneys was higher as for (18F)FB-RGD, which already is considered to be rather lipophilic. Anyway, (18F)FB-RGD was used to image brain tumour growth in a murine tumour model . In this model longitudinal microPET imaging allowed visualization and quantification of anatomical variations during brain tumour growth and angiogenesis. In addition, the effect of PEGylation was studied by comparing 64Cu-DOTA-RGD and 64Cu-DOTA-PEG-RGD (PEG, MW = 3.4 kDa) . As discussed above 64Cu-DOTA-RGD showed significant liver uptake. Thus, in this case, PEGylation reduced activity concentration in liver and small intestine and resulted in a faster blood clearance, while the tumour uptake as well as retention was not affected.
Dijkgraaf et al. studied the influence of linker variation on the targeting properties of an 111In-labelled DOTA-derivatised RGD-dimer. Linker variation did not affect affinity for alpha(v)beta3 as well as tumour uptake. Insertion of lysine or of glutamic acid resulted in enhanced retention in the kidneys. PEG4-insertion appeared to be the most suitable linker as compared with glutamic acid and lysine because it has the highest tumour/blood ratio and the lowest uptake in the kidney and liver.
Altogether, these studies revealed very different effects of PEGylation on the pharmacokinetics and tumour uptake of RGD-peptides which seems to strongly depend on the nature of the lead structure. However pharmacokinetic modifyers may be necessary in general to adjust especially lipophilicity and charge towards the desired pharmacokinetic properties. In some cases, however, radiolabelling strategies themselves can serve to modulate pharmacokinetics. Especially HYNIC-derivatisation for radiolabelling with 99mTc using hydrophilic coligands or DOTA-conjugation for other radiometals have shown to serve this purpose.
7. THE "MULTIMERISATION" APPROACH
Besides monomeric RGD-peptides also multimeric compounds presenting more than one RGD-site have been introduced. This "multimerisation" approach may result in an improved target affinity and prolonged target retention mainly due to an increased apparent ligand concentration and/or, especially by lager molecules, due to strong cooperative binding. Janssen et al. synthesized a dimeric RGD-peptide by coupling two cyclo(-RGDfK) via a glutamic acid linker. For radiolabelling DOTA or HYNIC were conjugated to the free amino function of the linker moiety. The dimeric 99mTc-HYNIC-E-(c(RGDfK))2 revealed a 10-fold higher affinity for the alpha(v)beta3 integrin as the monomeric 99mTc-HYNIC-c(RGDfK). Moreover, also activity retention in the tumour was improved compared with the monomeric compound. However, activity retention was also high in kidneys.
A more systematic study on the influence of multimerisation on receptor affinity and tumour uptake was carried out by the groups of Wester and Kessler . They synthesized a series of monomeric, dimeric, tetrameric and octameric RGD-peptides. These compounds contain different numbers of c(RGDfE) peptides which are connected via PEG linker and lysine moieties, which are used as branching units. Labelling was based on a chemoselective oxime formation between an aminooxo function at the peptide site and a 18F-labelled aldehyde. They found an increasing binding affinity in the series monomer, dimer, tetramer and octamers in an in vitro binding assay (Figure 2). Initial PET images resulting from a clinical PET scanner confirmed these findings. The image of mice with both a receptor positive and a receptor negative melanoma showed an increasing activity accumulation only in the receptor positive tumour in the series monomer, dimer and tetramer. Moreover, PET studies comparing a tetrameric structure containing four c(RGDfE) peptides with a tetrameric compound containing only one c(RGDfE) and three c(RaDFE) peptides (which do not bind to the alpha(v)beta3 integrin) showed for the pseudo monomeric tetramer a 3-fold lower activity accumulation in the tumour as for the "real" tetramer, indicating that the higher uptake in the tumour is due to multimerisation and not based on other structural effects.
In another study, a dimeric cyclic RGD peptide E(c(RGDyK))2 was labelled by conjugating a 4-(18F)fluorobenzoyl moiety to the amino function of the glutamate . The dimeric RGD peptide demonstrated significantly higher tumour uptake and prolonged tumour retention in comparison with a monomeric RGD peptide analogue (18F)FB-c(RGDyK). Moreover, the dimeric RGD peptide had predominant renal excretion, whereas the monomeric analogue was excreted primarily via the biliary route. Thus, the authors conclude that the synergistic effect of polyvalence and improved pharmacokinetics may be responsible for the superior imaging characteristics of (18F)FB-E(c(RGDyK))2. To improve labelling yields in a further study a mini-PEG spacer (11-amino-3,6,7-trioxaundecanoic acid) was introduced . This resulted in an improved amino function reactivity and thus, in an increased overall radiolabelling yield. Moreover, (18F)FB-mini-PEG-E(c(RGDyK))2 showed reduced renal and comparable tumour uptake as found for (18F)FB-E(c(RGDyK))2. The same approach was used to synthesize a tetrameric RGD-peptide . In this case the tetrameric (18F)FB-mini-PEG-E{E(c(RGDyK))2}2 showed no increased in vitro binding affinity as compared to the monomer and dimer. However, dynamic animalPET studies demonstrated an increased tumour uptake up to 120 min p.i. compared with (18F)FB-mini-PEG-E(c(RGDyK))2. Unfortunately, similar increase in tracer concentration is also found in kidneys, liver and muscle resulting in comparable tumour/background ratios for both compounds.
Similar effects as for the 18F-labelled dimer (18F)FB-E(c(RGDyK))2 have been found for dimeric 64Cu-labelled analogues . In contrast to (18F)FB-mini-PEG-E{E(c(RGDyK))2}2, the comparison with the tetrameric (64Cu)DOTA-E(E-c(RGDyK)2)2 showed significantly higher integrin binding affinity for the tetramer than the corresponding monomeric and dimeric RGD analogues, most likely due to a polyvalence effect. Again tumour uptake was rapid and high, and the tumour washout was slow. The positive effect of "multimerisation" on tumour uptake is further confirmed by introduction of a 64Cu-labelled octrameric RGD-peptide as well as 111In-labelled monomeric, dimeric, and tetrameric analogues . However, also in this case uptake in different organs including kidneys and muscle was increased indicating that a favourable balance between binding epitope density and tracer size is important for the design of the optimal tracer.
As described the scaffolds of the multimers are based on glutamate or lysine linker moieties. However, most recent approaches uses a regioselectivity addressable functionalised template (RAFT) or dendrimers as scaffold for the synthesis of multimeric RGD-peptides. For the (99mTc)RAFT-RGD four cyclic RGD sequences are tethered on a cyclodecapeptide platform and labelled with 99mT using the tricarbonyl strategy. The in vivo biodistribution studies using two different murine tumour models showed that the tumour uptake of the tetramere is significantly higher as the tumour uptake of the corresponding monomer. The other approach uses the 1,3-dipolar cycloaddition for conjugating the cyclic RGD-peptides to the branching unit which are coupled with DOTA for 111In-labelling. Monomeric, dimeric and tetrameric peptides have been synthesized. In vitro binding studies showed for the tetrameric compound higher alpha(v)beta3 affinity compared with the monomer and dimer. Moreover, tracer uptake in the tumour increases in the series monomer, dimer and tetramer. However, increasing activity concentration is also found in a variety of organs including kidneys, liver and intestine.
Altogether, in many cases the "multimerisation" approach lead to increased binding affinity and tumour uptake as well as retention of the tracer and can, by using appropriate linker moieties and molecular size, improve the pharmacokinetics of peptide based tracer. An overview of multmerisation approaches is shown in table 4.
8. HETEROMULTIMERS
It is obvious that tumours over-express a variety of different receptors. By designing compounds which combine the binding epitopes of these receptors a new class of tracers for multireceptor tumour targeting may become available. Such heteromultimeric systems may enhance tracer accumulation by taking advantage of the heterogeneity of receptor expression on target cells (targeting of the cumulative receptor density). E.g. Reubi and co-worker have studied over-expression of peptide receptors on breast cancer and neuroendocrine tumours and postulated that by combination of binding epitopes for the gastrin-releasing peptide receptor and the neuropeptide Y receptor approx. 93% of breast carcinoma and their lymph node metastases should be detectable. Furthermore, heterodimers offer the possibility to addressing successive biochemical processes within the cell, e.g. using the first bioactive structure as a vehicle and addressing unit and the second one as effector. Some of these strategies are currently evaluated using RGD-sequences as ligands.
De Jong et al. conjugated cyclo(-Arg-Gly-Asp-dPhe-Lys-) via a DTPA moiety with octreotate and labelled it with 111In. This heterodimer showed comparable high affinity and selectivity for the somatostatin receptor subtype 2 (sst2) and the integrin alpha(v)beta3 as the monomers. However, tracer accumulation in the tumour was mainly determined by binding of the compound to sst2. Although the authors explained this by a higher affinity of octreotate for sst2 than of the RGD-peptide for alpha(v)beta3, a higher sst2 density and fast internalization of sst2 could also significantly contribute to this finding. Anyway, based on these data a new approach was studied where the octreotate part of the radiolabelled heterodimeric peptide was used as a selective shuttle transporting the RGD-peptide, which is known not only to bind to integrins but also to induce apoptosis via caspase-3 activation , into the tumour cell. This combination approach is expected to increase the therapeutic efficacy of somatostatin-based receptor-targeted radionuclide therapy . Initial in vitro studies showed an increased caspase-3 activation and cell death after incubation with the hybrid peptide . However, in further studies high renal uptake of RGD-111In-DTPA-octreotate was found which let the authors conclude that this compound is not suitable for radionuclide therapy .
9. CLINICAL EVALUATION
The promising preclinical data of (18F)Galacto-RGD were the basis for initial clinical evaluation of this tracer in a small number of tumour patients. Nine patients with malignant melanoma, sarcoma, osseous metastasis from renal cell carcinoma and a villonodular synovitis were imaged with PET . In these tumours a very variable uptake was observed. Standard uptake values (SUVs) ranged from 1.2 to 10.0. While for one melanoma patient multiple lesions were detected by a (18F)FDG scan, indicating viable tumour cells, no (18F)Galacto-RGD uptake was found. For other patients similar uptake patterns were observed for both tracers. These high inter- as well as intraindividual variances in tracer accumulation in the different lesions indicate great diversity in alpha(v)beta3 expression and demonstrate the importance of non-invasive tools for planning and controlling of corresponding alpha(v)beta3-targeted antiangiogenic therapies.
Further biodistriubtion and dosimetry studies confirmed the favourable pharmacokinetics of (18F)Galacto-RGD with rapid renal excretion and elimination from the blood pool. Background activity in lung and muscle tissue was low and the calculated effective dose found was approx. 19 �Sv/MBq which is very similar to a (18F)FDG scan. The metabolic stability analysed from blood samples was high up to 120 min after tracer injection. Tumour kinetics were consistent with a two-tissue compartment model with reversible specific binding. Distribution volume values were in average four times higher for tumour tissue than for muscle tissue. The data suggest that there was only minimal free and bound (specific or unspecific) tracer in muscle tissue. Thus, (18F)Galacto-RGD demonstrates a highly favourable biodistribution in humans with specific receptor binding.
In a recent study 19 patients with solid tumours (musculoskeletal system n=10, melanoma n=4, head and neck cancer n=2, glioblastoma n=2, breast cancer n=1) were examined with PET using (18F)Galacto-RGD before surgical removal of the lesions . Tumour tissue sections from representative areas with low as well as intense SUVs were collected and imunohistochemistry was performed. Intensity of staining and the microvessel density of alpha(v)beta3-positive vessels were determined and correlated with SUV and tumour/blood-ratios. For 17 of the 19 lesions varying tracer accumulation with SUVs ranging from 1.2-10.0 were found. But more important, the correlation of SUV and tumour/blood-ratios with the intensity of immunohistochemical staining as well as with the microvessel density were significant. Moreover, immunohistochemistry confirmed lack of alpha(v)beta3 expression in normal tissue and in the two tumours without tracer uptake.
Two recent studies investigated the feasibility of using (18F)Galacto-RGD in specific patient groups. In eleven patients with squamous Cell Carcinoma 10 out of 12 tumours were identified, which confirmed alpha(v)beta3 expression mainly on tumour vessels by ex vivo Immunhistochemistry. Comparable results were obtained in 19 patients with breast cancer with predominant expression of alpha(v)beta3 integrin on microvessels two examples of images and corresponding immunhistochemistry are shown in Figure 3). In an additional study Beer et al compared (18F)Galacto-RGD and (18F)FDG uptake in 18 patients with different primary or metastatic cancers, whereby no correlation between glucose metabolism ((18F)FDG uptake) and alpha(v)beta3 expression could be found .
These studies demonstrate that molecular imaging of alpha(v)beta3 expression with (18F)Galacto-RGD in humans correlates with alpha(v)beta3 expression as determined by immunohistochemistry. The variable tracer uptake which is in correlation with variable alpha(v)beta3 expression shows the value of non-invasive techniques for appropriate selection of patients entering clinical trials of alpha(v)beta3-targeting therapies. PET with (18F)Galacto-RGD might therefore be used as a new marker of activated endothelial and tumour cells and for individualized planning of therapeutic strategies with alpha(v)beta3-targeted drugs.
The second RGD based tracer that has been evaluated in humans is 99mTc-NC100692. In a proof of concept study 16 patients with equiviocal mammographic findings and 4 patients with benign lesions were included. Nineteen of 22 histopathological confirmed malignant lesions were detected using 99mTc-NC100692 scintigraphy. The use of 99mTc-NC100692 in subjects with breast cancer was well tolerated and indicates the potential of this tracer for tumour imaging, however immunhistoligical correlation with alpha(v)beta3 expression was not reported .
10. PERSPECTIVE
In conclusion, great efforts have been made to develop radiolabelled RGD peptides for the non-invasive determination of the alpha(v)beta3 expression for monitoring angiogenetic processes. The clinical data available so far show that by using (18F)Galacto-RGD alpha(v)beta3 expression in tumours can be monitored and further clinical studies will have to provide data on the potential of this imaging technique in various clinical situations. Recent approaches towards multimers and alternative radiolabelling strategies show great potential in vitro and in preclinical models with significant improvement of targeting and even the potential of therapeutic application. Whether this can be translated into a clinical setting still has to be shown.
11. ACKNOWLEDGEMENT
Hans-Jürgen Wester, is kindly acknowledged for supplying some of his groups unpublished data.
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Key Words: Angiogenesis, Radiolabelled Rgd-Peptides, Integrin alpha (v)beta3, Tracer Techniques, Molecular Imaging, Review
Send correspondence to: Clemens Decristoforo, Clinical Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria, Tel: 43512504 80951, Fax: 43512504 6780951, E-mail:Clemens.Decristoforo@uki.at