Radionuclides and carrier molecules for therapy

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Phys. Med. Biol.41 (1996) 1905–1914. Printed in the UK

Radionuclides and carrier molecules for therapy

Jamal ZweitJoint Department of Physics, Institute of Cancer Research and Royal Marsden NHS Trust,Downs Road, Sutton, Surrey, SM2 5PT, UK

Received in accepted form 23 April 1996

Abstract. Although radionuclide therapy has been around for a long time, this modality ofcancer treatment has been limited mainly to the use of [32P]-phosphate and [131I]-sodium iodide.The last few years, however, have seen an increased interest in this area due to new developmentsof radionuclides and carrier molecules that may provide selective targeting of tumour sites. Thepotential of this technique can be further realized if the radionuclide is carefully selected to matchboth the localization of the carrier molecule and tumour morphology. This paper briefly reviewsradionuclides in current use and potential candidates for targeted therapy. Decay characteristics,production methods and relevant chemical properties are discussed.

1. Introduction

Cancer treatment with unsealed radionuclides is still the least commonly used method ofthe radiotherapy modalities compared with external beam therapy and sealed source therapy(brachytherapy). It involves the use of unsealed radioactive sources, in a certain chemicalform, which, when administered to the patient, localize within the tumour. A potentiallyexciting development in this area is targeted radionuclide therapy which utilizes a carriermolecule (such as a monoclonal antibody (MAb)) to deliver the radionuclide to the tumoursite. In principle this technique can deliver radiation doses selectively in target tissues whilstsparing critical normal organs (Hoefnagel 1991).

Table 1. Examples of clinically used radionuclides in cancer therapy.

Radioniclide Pharmaceutical Clinical use

32P NaH2PO4 Polycythaemia vera32P CrPO4 Intracavitary89Sr SrCl2 Bone metastases90Y Microspheres Hepatic tumours90Y Antibodies Various tumours114mIn Lymphocytes Lymphoma131I NaI Diff thyroid carcinomas131I mIBG Neural crest tumours131I Antibodies Various tumours153Sm EDTMP Bone metastases186Re HEDP Bone metastases131I Lipiodol Hepatic tumours

Examples of current clinical applications of radionuclide therapy in cancer are given intable 1. The most commonly used therapeutic radiopharmaceuticals are still [32P]-phosphate

0031-9155/96/101905+10$19.50c© 1996 IOP Publishing Ltd 1905

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and [131I]-sodium iodide for the treatment of polycythaemia vera and differentiated thyroidcarcinoma respectively.

2. Radionuclide selection

The choice of a particular radionuclide for therapy is based on the following:

(i) radionuclide physical and chemical properties,(ii) production methods and(iii) biological behaviour, particularly if it suffersin vivo dissociation from the carrier

molecule.

The physical properties to consider include the radionuclide half-life, its mode ofdecay and the type, energy and intensity of the radiation emitted. The chemical formin which the radionuclide is used ranges from the simple ion (such as I− or Sr2+) to morecomplex agents such as MAbs. The latter form necessitatesin vivo kinetic inertness of theradiopharmaceutical towards dissociation, substitution or redox reactions. The importanceof production methods reflects essential qualities such as radionuclide and chemical puritiesand specific activity. The latter is more critical, for example, in receptor binding agentssuch as MAbs.

3. Modes of decay

Radionuclides considered for therapeutic applications undergo the following modes of decay:(i) beta, (ii) alpha and (iii) electron capture or isomeric transition, leading to the emission ofAuger and Coster–Kronig (C–K) electrons. Although potentially possible, positron-emittingradionuclides have yet to be explored for therapeutic use. The different types of decay emitparticles with different energies, ranges and relative biological effectiveness (RBE). The typeof emitted particle required for a particular application will depend on the distribution ofthe radiopharmaceutical relative to the target sites (Wessels and Rogus 1984, Adelstein andKassis 1987, Humm and Cobb 1990, Volkertet al 1991). Therefore, one needs to match theparticle energy (and hence range) to the cellular distribution of the carrier molecule, namelylocalization on the surface (β), in the cytoplasm (β/α) or in the nucleus (Auger and C–Kelectrons). The emphasis in this paper will be onβ-emitting radionuclides, together witha brief description ofα-emitters. The use of Auger-electron emitters is described in thisissue in the paper by O’Donoghue and Wheldon (1996). The potential of targeted therapyusing compounds labelled withα-emitters is also described in this issue in the paper byVaidyanathan and Zalutsky (1996). Decay data of radionuclides were taken from theTableof Isotopes(Lederer and Shirley 1978) and from ICRP 38 (Sowby 1983).

4. α-Emitting radionuclides

α-Decay occurs predominantly among heavy elements (Z > 82). α-Particles are high-energy helium nuclei (4He) with high (about 100 keVµm−1) linear energy transfer (LET).This implies that the number ofα-decays needed per cell killed is about a factor of 1000 lessthan that ofβ-decays (Humm and Cobb 1990).α-Particles are mono-energetic and deposittheir energy over short ranges (typically 40–80µm or several cell diameters for 5–8 MeVparticles). The effectiveness ofα-emitting radionuclides is likely to require binding of thecarrier molecule to most cancer cells within the tumour.

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Table 2. α-Particle emitting radionuclides for targeted therapy.

Half-life Averageα-energy X/γ -ray emissionsRadionuclide (h) (MeV) (keV) Production

211At 7 6.8 77–92 Cyclotron212Bi 1 7.5 Generator225Ac 240 6.4 100 Generator246Cf 36 6.7 Not developed252Fm 23 7.0 Not developed255Fm 20 7.0 Not developed

To date only a fewα-emitting radionuclides have been considered for targeted therapy(table 2). Astatine-211 (211At) and bismuth-212 (212Bi) are the two radionuclides whichhave been studied the most.

4.1. Astatine-211

211At (t1/2 = 7.2 h) decays by two modes, both indirectly leading to stable207Bi. Theα-decay leads to the emission of two particles with an average energy of 6.8 MeV. Theelectron capture results in the emission of polonium-211 (211Po) x-rays with energies of77–92 keV. These latter emissions provide possibilities for tomographic imaging using agamma camera (Turkingtonet al 1993).

211At is produced by the209Bi(α, 2n) reaction using a 28 MeV incident beam and isextracted from the bismuth target by dry distillation (Brownet al 1986, Zalutsky and Narula1988). The short half-life necessitates production at an on-site or a regional cyclotron.

A number of potential therapeutic agents including MAbs (Zalutskyet al 1989),methylene blue (Link and Carpenter 1992) andmeta-astato-benzylguanidine (Vaidyanathanand Zalutsky 1992) have been labelled with211At and encouraging results have beenobtained in pre-clinical studies. Another compound that could be labelled with211At is thethymidine analogue deoxyuridine for DNA targeting. It should be possible to synthesize[211At] astato-deoxyuridine in a no-carrier-added form using methods similar to those forits halogen analogue iodo-deoxyuridine (Baranowska-Kortylewiczet al 1994).

4.2. Bismuth-212

212Bi (t1/2 = 1 h) also has two decay modes, both indirectly leading to stable208Pb. Oneroute is byβ-decay to212Po followed by emission of 8.8 MeVα-particles. The second isby α-decay with an energy of 6.1 MeV.

212Bi is produced in a radionuclide generator using228Th, 224Ra or 212Pb as the parentradionuclide. 224Ra with a half-life of 3.8 days appears to be the most useful for routineuse (Atcheret al 1988). Several212Bi-labelled MAbs have been evaluated in pre-clinicalstudies (Kozaket al 1986, Mackliset al 1988). More recently212Bi-DTPA (Palayouret al1993) and212Bi-EDTMP (Hassfjellet al 1994) have also been evaluated pre-clinically asagents for inducing apoptosisin vitro and for targeting bone metastases respectively.

Despite the high level ofin vitro and in vivo cytotoxicity demonstrated withα-particleemitters, the short half-lives of212Bi and 211At may impose restrictions on their clinicaluse. Longer-livedα-emitting radionuclides are suggested in table 2. Perhaps radionuclidesof fermium (252Fm, t1/2 = 23 h; 255Fm, t1/2 = 20 h) and actinium-225 (225Ac, t1/2 = 240 h)

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(Geerlingset al 1993) may allow more flexibility in the design of a carrier, provided thatproduction methods for these radionuclides are developed.255Fm has already been suggestedby Bigler and Zanzonico (1988).

5. β-Emitting radionuclides

Negatively charged electrons are emitted from the nucleus asβ-particles with a continuousenergy spectrum ranging from zero up to a maximum. The average energy of aβ-particleis about one-third of its maximum energy. The range ofβ-particles can be calculated bythe method of Cole (1969). Approximately, the maximum range (in millimetres) in softtissue is equal to the maximum energy (in mega-electron-volts) multiplied by five.

Clinical radionuclide therapy has so far been exclusively practiced usingβ-emittingradionuclides.131I and 32P have been the most commonly used radionuclides, largely dueto their availability at low cost rather than any rational systematic analysis of their suitabilityfor a particular therapy.β-emitters offer a wide choice of candidates in terms of particleenergy (range) and chemical properties. It is useful to classifyβ-emitting radionuclides intothree groups according toβ-particle energy and hence range. As regards physical properties,these are the two parameters which have to be matched to the size of the tumour. The half-life and chemical properties, on the other hand, are related to the pharmacokinetics andmetabolism of the carrier molecule.

Tables 3–5 list the physical properties of three groups ofβ-emitting radionuclides,classified according to their average energy and mean range. The tables include examplesof radionuclides in clinical use (32P, 131I, 90Y, 89Sr, 153Sm and186Re), others which havebeen investigated in pre-clinical studies (109Pd, 111Ag, 47Sc, 67Cu and105Rh) and potentialcandidates that have yet to be investigated (76As, 77As, 142Pr and143Pr).

5.1. Low-energyβ-emitters

The radionuclides included in table 3 (Eavg = 0.08–0.18 MeV, mean range 0.4–0.9 mm)are best suited for small tumours (d ' 1–2 mm) (Howellet al 1989). 131I is the mostfamiliar and the only radionuclide in this group that has been used clinically. Upon closeexamination, however, one finds that the physical properties of this radionuclide are farfrom ideal. Its total equilibrium dose constant for penetrating radiation (1p) is higher thanthe respective values for the rest of the group by up to a factor of 11. This is due tothe fact that two-thirds of the131I decays result in medium-to-high-energy (284 (6%), 364(81%), 637 (7%) and 723 keV (2%))γ -emissions. This results in sub-optimum deliveryof radiation dose to the tumour and significant irradiation of surrounding normal tissues.The total equilibrium dose constant for non-penetrating radiation (1np) is similar for all theradionuclides listed.

A good candidate in this group is105Rh, with a half-life of 35 h. Rhodium complexesare kinetically inert and are expected to be very stablein vivo (Johnet al 1989, Pillaiet al1990). The weighted averageβ-energy of105Rh is similar to that of131I (0.152 and 0.182respectively). Rhodium-105 is produced at high specific activity using104Ru(n, γ )105Rufollowed by β-decay to 105Rh (Grazman and Troutner 1988). An unsolved problemwith current production methods is the high level of Ru impurity associated with theradiochemical separation method used. This is a major problem insofar as the presenceof Ru will always compete with105Rh in chelation reactions.

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Table 3. Low-energyβ-emitting radionuclides. (1np and 1p are the total equilibrium doseconstants for non-penetrating and penetrating radiations respectively.)

Half-life Average energy Mean range 1np 1p

Radionuclide (days) (MeV) (mm) (g Gy MBq−1 h−1) (g Gy MBq−1 h−1)

199Au 3.1 0.082 0.41 0.082 0.051169Er 9.3 0.101 0.51 0.06177Lu 6.7 0.133 0.67 0.085 0.02067Cu 2.6 0.141 0.71 0.089 0.066105Rh 1.5 0.152 0.76 0.088 0.045161Tb 6.9 0.154 0.77 0.113 0.02047Sc 3.4 0.162 0.81 0.093 0.062131I 8.0 0.182 0.91 0.109 0.219

Table 4. Medium-energyβ-emitting radionuclides.

Half-life Average energy Mean range 1np 1p

Radionuclide (days) (MeV) (mm) (g Gy MBq−1 h−1) (g Gy MBq−1 h−1)

77As 1.6 0.228 1.2 0.131 0.005153Sm 1.9 0.229 1.2 0.156 0.035159Gd 0.8 0.311 1.6 0.173 0.029143Pr 13.6 0.314 1.6 0.181198Au 2.7 0.315 1.6 0.188 0.233111Ag 7.5 0.360 1.8 0.204 0.015109Pd 0.5 0.361 1.8 0.251 0.007186Re 3.8 0.362 1.8 0.198 0.012149Pm 2.2 0.364 1.8 0.210 0.006

Table 5. High-energyβ-emitting radionuclides.

Half-life Average energy Mean range 1np 1p

Radionuclide (days) (MeV) (mm) (g Gy MBq−1 h−1) (g Gy MBq−1 h−1)

165Dy 0.1 0.451 2.2 0.256 0.01589Sr 50 0.580 2.5 0.336166Ho 1.1 0.666 3.2 0.398 0.01732P 14 0.695 2.9 0.400188Re 0.71 0.764 3.5 0.447 0.033114mIn 50 0.777a 3.6 0.443 0.056142Pr 0.79 0.809 3.7 0.464 0.03490Y 2.7 0.935 3.9 0.53976As 1.1 1.00 5.0 0.600 0.245

a From 114In daughter.

5.2. Medium-energyβ-emitters

Of the radionuclides listed in table 4 (Eavg = 0.23–0.36 MeV, mean range 1.2–1.8 mm),only 153Sm (labelled to EDTMP) and186Re (labelled to HEDP) have so far been used inclinical trials (Farhanghiet al 1992, de Klerket al 1994) for the treatment of pain frombone metastases. The physical properties of143Pr look very attractive for targeted therapy,the 13.6 day half-life being well matched to the prolonged tissue kinetics of MAbs. Themean particle range from itsβ-emission is nearly twice that of131I, which could make

1910 J Zweit

it more effective in overcoming the non-uniformity problem associated with MAb uptakein solid tumours. The radionuclide can be produced at high specific activity in a reactorusing indirect neutron activation through the142Ce(n, γ )143Ce→143Pr reaction. The specificactivity can be further increased by the use of an enriched142Ce target which will result inabout a factor of eight or nine (depending on the enrichment) increase in the yield of the143Ce intermediate. The specific activity will also be increased by significantly reducing theproduction of stable141Pr through the141Ce parent. This co-production of stable isotopesis an often overlooked source of undesired carrier.

77As is another radionuclide in this group that could be potentially useful. It has a 39 hhalf-life that is compatible with the kinetics of a number of compounds including MAbs.The 1p value for77As is very small (0.005) and hence irradiation of normal tissues due topenetrating radiation will be insignificant. The radionuclide can be produced in high specificactivity by the (n, γ, β) reaction on enriched76Ge. Radiochemical separation methods usedfor the purification of the positron emitter71As (Zweit 1989) can be adapted to the separationof 77As from a 76Ge target. One possible application for As radionuclides is to substituteAs for phosphorus in oligonucleotide synthesis, thereby providing possibilities for anti-sense DNA/RNA targeting with radiolabelled molecules. Similarity in the physiochemicalproperties of As and P has made such substitution possible and the feasibility of this approachhas already been demonstrated in a number of compounds (Emran and Phillips 1991).

5.3. High-energyβ-emitters

The radionuclides in table 5 (Eavg = 0.5–1.0 MeV, mean range 2.2–5.0 mm) are mosteffective in treating large tumours (d > 1 cm) (Howell et al 1989). Of the radionuclideslisted 32P, 89Sr and 90Y are in clinical use. A non-uniform distribution of radioactivityin tumours is a recognized problem and its effect on dosimetry has been investigated(Humm 1986, Howellet al 1989, Humm and Cobb 1990). As an example, Humm(1986) investigated the effect of differently sized ‘cold regions’ for199Au, 77As and 90Yrepresenting low-, medium- and high-energy particles respectively. The results suggest that,as the size of the cold region increases, higher energyβ-emitters are required to sterilizethe tumour. It was also concluded that, as the size of the tumour decreases, it becomesincreasingly more advantageous to use lower energyβ-emitters in order to minimize thedose administered to normal tissues (Humm 1986). Among the high-energyβ-emitters intable 5,76As is potentially a good candidate. It has a half-life of 26 h that is compatiblewith the pharmacokinetics of a number of compounds. It emits aβ-particle of 3 MeVmaximum energy. The radionuclide can be produced in a reactor by (n, γ ) reaction with across section of 4300 mbarn. It could also be produced by proton or deuteron bombardmentof enriched76Ge using a low-energy cyclotron.

6. Auger-emitting radionuclides

Radionulides which decay by electron capture or isomeric transition emit low-energy Augerand K–C electrons. Most of these electrons have very short range (< 1 µm) and thereforeare only of use in therapy if the source is attached to, or very close to, the cell nucleus. [125I]-IUDR is the most investigated therapeutic agent for DNA targeting of tumours (Sastry 1992).Platinum anti-tumour compounds labelled with193mPt or 195mPt have also been investigated(Howell et al 1994). Table 6 gives examples of Auger and K–C electron emitters which mayhave potential for short-range targeting. All the radionuclides listed have low1p valuesdue to photon emissions being weak or absent and most of them can be easily produced

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Table 6. Selected radionuclides that decay by electron capture or isomeric transition and emitlow-energy electrons (Auger and Coster–Kronig electrons).

Half-life Electron yield 1np 1p

Radionuclide (days) per decay (g Gy MBq−1 h−1) (g Gy MBq−1 h−1) Production

71Ge 11.2 4.2 0.003 0.002 Cyclotron103Pd 17 2.8 0.003 0.008 Cyclotron103mRh 0.04 2.3 0.022 0.001 Generator119Sb 1.6 4.4 0.015 0.013 Cyclotron125I 60 25a 0.011 0.024 Reactor131Cs 9.7 2.4 0.004 0.013 Generator165Er 0.42 2.4 0.005 0.021 Generator193mPt 4.3 26a 0.079 0.007 Reactor or

cyclotron195mPt 4.0 33a 0.105 0.044 Reactor

a Total electron yield (Auger plus Coster–Kronig electrons).

in a reactor or could be provided from generator systems. More detailed discussion on thepotential use of Auger emitters for targeted radionuclide therapy is given in the paper byO’Donoghue and Wheldon in this issue (O’Donoghue and Wheldon 1996).

7. The ‘cocktail approach’

The previous sections have concentrated on matching the tumour size with the physicalproperties of the radionuclide, in particular theβ-particle energy. Although it is essential totarget large tumours with high-energyβ-particles and small tumours with low-to-medium-energy particles, this would still fall short of achieving effective treatment. The first reasonfor this is that tumours are present in varying sizes and therefore selecting aβ-particlewith a range to match the largest tumour will have a minimum impact, in terms of energydeposition, on the smaller tumours. It has been shown, through mathematical modelling, thatthe probability of curing tumours smaller than the optimal diameter decreases progressivelywith decreasing size (O’Donoghueet al 1995). Another important issue is the problem ofnon-uniform distribution of the radiopharmaceutical within the tumour which will result inthe irradiation of fewer tumour cells when using a single-energy-range particle comparedwith a combination of particles with different energies/ranges. If, for example, high-energy,long-range particles (such as from32P) were used, then small tumours and metastases,6 1 mm in size, would be resistant to treatment because most of the disintegration energywill be deposited outside the tumour. On the other hand, if a short-range emitter was used(such as33P), areas which experience a reduced energy deposition and hence dose could actas foci for tumour recurrence. A combination of32P and33P is therefore useful and quitefeasible. Such a cocktail combines a short-range emitter (33P), which would inflict damageon small tumours, with a long-range emitter (32P), which would deal with larger tumoursand would also reduce the adverse effects of heterogeneity of radionuclide distribution.

The implication of this argument is that the use of a combination of particles withdifferent energies and ranges in a ‘cocktail’ of radionuclides would result in the irradiationof more tumour cells and therefore the overall energy deposition is higher and the therapyis more effective. For this approach to succeed, radionuclide cocktails must be made ofisotopes of the same element, especially when therapy is through a radiolabelled carriermolecule rather than just a simple radionuclide ion. Examples of radionuclides that can

1912 J Zweit

be used in a cocktail approach are listed in table 7. Optimum diameters (Dopt ) for acure probability of 0.9 were calculated for the differrent radionuclides from the model ofO’Donoghueet al (1995).

Table 7. Suggested radionuclides for the ‘cocktail approach’.

Radionuclide Half-life Optimum diameterpair (hours) (mm)

33P 600 0.632P 340 2366Ni 55 0.565Ni 3 3064Cu 13 3.066Cu 0.1 3972Zn 47 0.669m/gZn 14/1 13112Pd 20 0.7109Pd 14 7.0110Ag 6000 0.4111Ag 180 10.0

8. Matched radionuclide pairs for imaging/therapy

The dosimetry of radionuclide therapy relies on quantitativein vivo uptake measurementsof the therapeutic agents. These measurements can be best achieved by positron-emissiontomography (PET) imaging. In this issue Ott (1996) gives a detailed account of howimaging, particularly PET, can improve the accuracy of radionuclide therapy dosimetry.Here the idea of using radionuclide pairs (a positron and aβ-emitting radioisotope of thesame element) is highlighted. The use of a different radio-element, even when linked tothe same carrier molecule, could influence the biodistribution. Pre-therapy imaging with anisotope of the same element is therefore essential. Some examples of PET radionuclides,of which therapy analogues are included in tables 3–5, are64Cu, 71As, 72As, 83Sr, 86Y and124I. Of this group,64Cu looks extremely promising. It is one of very few radionuclideswhich combineβ−, β+ and Auger electron emissions in its decay. The biological effectsof 64Cu emissions in tumour cells have been found to be at least as lethal as those from theβ-emitter 67Cu (Apelgotet al 1989). This makes64Cu a good candidate radionuclide bothfor PET imaging and for targeted therapy.

9. Summary

The current trend in developing targeting compounds around existing, but not necessarilyideal, radionuclides such as131I, has to be re-considered. The full potential of targetedradionuclide therapy can only be realized if new developments in radionuclides and carriermolecules continue to expand.β-Emitting radionuclides offer a wide selection of particleenergies and chemical properties around which new carrier molecules can be developed.The use of64Cu for combined imaging/therapy should be explored further. The chemistryof copper is amenable to the development of compounds which could potentially exploitcertain targeting approaches such as redox mechanisms.

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How best to combine targeted radiotherapy with other treatment methods, such aschemotherapy, also warrants further investigation. A rationale for the use of combinedexternal beam radiotherapy, whole-body irradiation and targeted radionuclide treatment hasbeen proposed (Wheldon 1988, Aminet al 1993). As mentioned previously, some work isalready in progress in the area of chemo-Auger therapy using radiolabelled platinum drugs.This could, in principle, be extended to other DNA-targeting molecules labelled with Augerand possiblyα-emitting radionuclides.

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