Nuclear Medicine and Biology

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Neutron-activated theranostic radionuclides for nuclear medicine

Hun Yee Tan

^a

, Chai Hong Yeong

^b

, Yin How Wong

^b

, Molly McKenzie

^c

, Azahari Kasbollah

^d

, Mohamad Nazri Md. Shah

^e

, Alan Christopher Perkins

^f,

⁎

aSchool of Biosciences, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia

bSchool of Medicine, Faculty of Health and Medical Sciences, Taylor's University, 47500 Subang Jaya, Selangor, Malaysia

cSchool of Life Sciences, University of Dundee, DD1 4HN, United Kingdom

dMedical Technology Division, Malaysian Nuclear Agency, Bangi, 43000 Kajang, Selangor, Malaysia

eDepartment of Biomedical Imaging, University of Malaya Medical Centre, 59100 Kuala Lumpur, Malaysia

fRadiological Sciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom

a b s t r a c t a r t i c l e i n f o

Article history:

Received 10 July 2020

Received in revised form 8 September 2020 Accepted 22 September 2020

Available online xxxx Keywords:

Theranostics Neutron activation Radionuclide Nuclear medicine

Theranostics in nuclear medicine refers to personalized patient management that involves targeted therapy and diagnostic imaging using a single or combination of radionuclide (s). The radionuclides emit both alpha (α) or beta (β⁻) particles and gamma (γ) rays which possess therapeutic and diagnostic capabilities, respectively. How- ever, the production of these radionuclides often faces difﬁculties due to high cost, complexity of preparation methods and that the products are often sourced far from the healthcare facilities, hence losing activity due to radioactive decay during transportation. Subject to the availability of a nuclear reactor within an accessible distance from healthcare facilities, neutron activation is the most practical and cost-effective route to produce radionuclides suitable for theranostic purposes. Holmium-166 (¹⁶⁶Ho), Lutetium-177 (¹⁷⁷Lu), Rhenium-186 (¹⁸⁶Re), Rhenium-188 (¹⁸⁸Re) and Samarium-153 (¹⁵³Sm) are some of the most promising neutron-activated radionuclides that are currently in clinical practice and undergoing clinical research for theranostic applications. The aim of this paper is to review the physical characteristics, current clinical applications and future prospects of these neutron activated radionuclides in theranostics. The production, physical properties, validated clinical applications and clinical studies for each neutron-activated radionuclide suitable for theranostic use in nuclear medicine are reviewed in this paper.

Contents

1. Introduction . . . 56

2. Neutron activation . . . 56

3. Theranostics . . . 56

4. Commonly used neutron-activated radionuclides for nuclear medicine theranostics . . . 57

4.1. Holmium-166 . . . 57

4.2. Lutetium-177 . . . 60

4.3. Rhenium-186 . . . 61

4.4. Rhenium-188 . . . 62

4.5. Samarium-153 . . . 62

5. Recent developments of neutron-activated theranostics radionuclides for clinical applications . . . 63

5.1. Gastroenteropancreatic neuroendocrine tumors . . . 63

5.2. Bone metastasis . . . 63

5.3. Radiosynovectomy . . . 63

5.4. Head and neck cancer . . . 63

5.5. Non-melanoma skin cancer. . . 64

5.6. Liver cancer. . . 64

5.7. Malignant airway blockage and malignant biliary stricture. . . 64

5.8. Spinal cancer . . . 64

⁎ Corresponding author at: Radiological Sciences, School of Medicine, University of Nottingham, Nottingham NG7 2UH, United Kingdom.

E-mail address:[email protected](A.C. Perkins).

Contents lists available atScienceDirect

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / n u c m e d b i o

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6. Conclusions . . . 64

Abbreviations . . . 65

Acknowledgements . . . 65

References . . . 11

1. Introduction

The scope of nuclear medicine has expanded over the last decade due its capabilities in providing a wide range of both diagnostic imaging and targeted therapy. Recent advances in radiopharmaceuticals and nanotechnology has led to the evolution of a newﬁeld of nuclear medicine, known as theranostics. Theranostics provides a transition from conventional nuclear medicine to contemporary personalized or precision medicine. It uses molecular targeting vectors (such as receptor binding peptides and monoclonal antibodies (mAbs)) labeled with diagnostic and therapeutic radionuclide(s), to acquire diagnostic images as well as to deliver a therapeutic radiation dose to the target tissues.

This can be achieved by either using a theranostics radionuclide that emits both therapeutic (e.g.αorβ⁻) and diagnostic (e.g.γor positron) radiations, such as¹³¹I,¹⁵³Sm,¹⁶⁶Ho,¹⁷⁷Lu,¹⁸⁶Re and¹⁸⁸Re; or incorpo- rating two radionuclides (one for imaging and another for therapy) into the same theranostics radiopharmaceutical formulation. The diagnostic imaging enables determination of the subtype of the disease, its progression, and the speciﬁc characteristics of a patient. This information allows decisions to be made on the quantity, timing, type of drugs and choice of therapy procedures for personalized patient treatment, as well as to monitor early response to treatment and predict efﬁcacy.

There are several methods for producing medical radionuclides. The most common ones include neutron activation in a nuclear reactor or by particle acceleration via a cyclotron, synchrotron, or linear accelerator.

In the case of radionuclides produced by using a radionuclide generator one of the previously mentioned methods is used to produce the parent radionuclide [1]. This review only focuses on theranostic radionuclides that are produced via the method of neutron activation in a nuclear reactor. One of the classic examples of such a radionuclide is¹³¹I which has been used for more than 6 decades in the form of sodium iodide for the diagnosis and treatment of thyroid cancer [2].¹³¹I emits both therapeuticβ⁻particles and diagnosticγ-rays and it primarily targets the thyroid cells, with little uptake or effect on the rest of the body. In this way iodine is a radionuclide that serves a benchmark that other radionuclides can be compared to in terms of both functionality and cost effectiveness. The aim of this paper is to review the physical characteristics, current applications, and future prospects of neutron-activated theranostic radionuclides.

2. Neutron activation

Neutron activation is a preferred method for radionuclide production due to its cost-effectiveness, availability, and capability in producing a wide range of radionuclides. Currently, there are 220 operational research reactors in the world according to the International Atomic En- ergy Agency (IAEA) research reactor database [3]. However, the number of reactors capable of producing medical radionuclides is far less than thisfigure (96 nuclear research reactors [3]) and some have faced severe operational difficulties and production outages in recent years. Neutron activation describes the process in which a stable nuclide becomes radioactive after bombardment by a neutronflux. This occurs when atomic nuclei capture free neutrons, becoming heavier and entering excited states. The excited nucleus often decays immediately by emitting gamma radiation or particles such asα,β⁻,fission products and neutrons. The reaction is usually written as (n,γ) or (n,x) reaction, where x indicates the emitted particles [4].Fig. 1shows the basic structures of a nuclear research reactor and an example of a (n,γ) reaction.

Due to its inherent accuracy, sensitivity and simplicity, neutron activation has been extensively used in many applications including medical radionuclide production [5]. Two important factors in choosing a suitable radionuclide for medical applications are cost and availability.

The costs of the elemental targets, radiochemical processing, and reactor operation, including volume and time of irradiation, are among the factors that determine the radionuclide production cost. The radionuclide decay characteristics such as the physical half-life, abundance percentage, types and energies of radiation emissions also play a vital role in the effectiveness of the diagnostic/therapeutic application [6]. The activity, A in Becquerel (Bq) of a radionuclide produced via neutron activation can be calculated using Eq.(1)[6].

A¼Nσϕ1–e^–λ^t

ð1Þ

where:

N = number of target atoms

σ= cross-section (1 b = 10⁻²⁸m²or 10⁻²⁴cm²) ϕ= neutronﬂux

λ= decay constant = 0.693/T1/2

T_1/2= half-life t = time of irradiation

Most of the radionuclides produced in a research reactor are irradiated by thermal neutronﬂux (at levels between 10¹¹and 10¹⁴n/

cm²/s⁻¹) due to its simple production process and high yield [7]. In addition, many elemental targets do not require further chemical separa- tion of the target and product after activation.Table 1shows a list of medical radionuclides produced from stable targets by direct (n,γ) neutron activation, their physical characteristics, and current clinical applications. The wide availability of nuclear research reactors has encouraged many countries to produce radiopharmaceuticals locally so that they can be supplied to nearby healthcare facilities with more affordable price.

Although many radionuclides can be produced via neutron activation as listed inTable 1, factors such as short (less than few hours) or long (more than several days) physical half-lives, unstable decay products, absence ofγor positron emission for diagnostic imaging, too highγ-rays energy (unnecessary high dose to patient and personnel) and very low cross-section value (producing radionuclides with a spe- ciﬁc activity that are too low to be useful for therapy) eventually make those radionuclides unsuitable for theranostic applications [8]. There- fore, after considering all the factors above,¹⁶⁶Ho,¹⁷⁷Lu,¹⁸⁶Re,¹⁸⁸Re and¹⁵³Sm are the radionuclides that fulﬁll the criteria for theranostics use.

3. Theranostics

The term“theranostics”was introduced by John Funkhouser in 2002 [9] to describe developments in science to establish more speciﬁc and individualized therapies for various pathologies uniting the applications of diagnosis and therapy into a single agent. This approach has led to a promising therapeutic paradigm involving diagnosis, drug delivery and monitoring of treatment response [10]. Nevertheless, the fundamental principle of theranostics can be traced back to 1940's after

131I wasﬁrst used by Glenn Seaborg and John Livingood at the Univer- sity of California, Berkeley for the diagnosis and treatment of thyroid cancer [2,11].¹³¹I emits both therapeuticβ⁻particles and diagnostic γ-rays, which is a classic example of theranostics agent.¹³¹I targets

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primarily to the thyroid cells, whereby the radiation can destroy the thyroid glands and any other thyroid cells (including cancer cells) that uptake the iodine, with little effect on the rest of the body [12]. The usage of theranostics agent has been constantly expanding, and subse- quently playing an important role in nuclear targeted therapies, speciﬁcally in patients with advanced neuroendocrine tumours (for example gastroenteropancreatic tumours), pheochromocytoma, bronchopulmonary neuroendocrine tumours and neuroblastomas [13–20]. Additionally, radioligand therapies in metastatic melanoma and metastatic prostate cancer have presented encouraging results [21–25].

Theranostic radionuclides can be used as a diagnostic agent when administered at a lower activity to determine the location and state of disease prior to treatment. Hybrid single photon emission computed tomography/computed tomography (SPECT/CT) or positron emission tomography/computed tomography (PET/CT) imaging can be performed to assess the biodistribution and uptake to determine the optimum therapeutic activity required and to predict treatment outcome [26,27]

. As stated by Qaim [8], an ideal theranostic radionuclide should have appropriate biochemical reactivity and decay properties. He further elabo- rated that the radionuclide should have a physical half-life between 6 h to 7 d, medium to high linear energy transfer (LET) and sufﬁcient range in tissue for the treatment purpose. In addition, the ratio of non- penetrating to penetrating radiation must be high, and the radionuclide must decay into a short-lived or stable daughter. Furthermore, the radionuclide should provide an optimal and selective concentration along with prolonged retention in the tumours with minimum or no uptake in normal tissues [8]. A summary of the characteristics of neutron- activated theranostic radionuclides which are commercially available or currently undergoing clinical trials is presented inTable 2. WhileFig. 2 illustrates the clinical applications of currently available neutron- activated theranostic radiopharmaceuticals in different organs.

4. Commonly used neutron-activated radionuclides for nuclear medicine theranostics

4.1. Holmium-166

166Ho can be produced by neutron activation of¹⁶⁵Ho (100% natural abundance) which has a neutron cross-section of 64.7 b [28]; hence a large amount of¹⁶⁶Ho can be produced with relatively high speciﬁc activity of 2.28 GBq/mg following neutron activation at 4.2 × 10¹³n/cm²/s for 60 h [29]. It has a physical half-life of 26.8 h [30] and¹⁶⁶Ho is aβ⁻emitter (E_βmean= 0.66 MeV) that also emits 81 keVγ-rays suitable for gamma scintigraphy [31]. It is used for therapeutic applications such as radiosynovectomy and bone marrow ablation [6]. The penetration range of theβ⁻emissions from¹⁶⁶Ho in soft tissues is 2.2 mm on average, reaching a maximum depth of 10.2 mm [31]. The¹⁶⁶Ho is highly paramag- netic and has been used for both scintigraphy and magnetic resonance imaging (MRI) [32], which allowed biodistribution assessment and quantitative dosimetry analysis in patient post-procedural [33].

166Ho is a promising radionuclide for theranostics use due to its relatively high speciﬁc activity and short physical half-life, examples of therapeutic use include ¹⁶⁶Ho-1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetramethyl phosphonic acid (DOTMP) for bone marrow treatment in patients with multiple myelomas and¹⁶⁶Ho-ethylene diamine tetra(methylene phosphonate) (EDTMP) for metastatic bone pain palliation [34,35]. It has been reported that the toxicity proﬁle of

166Ho-DOTMP is acceptable although it results in higher marrow suppression compared with¹⁵³Sm-EDTMP due to the long range of

166Ho β- particles [36,37]. ¹⁶⁶Ho-1,2-propylene di-amino tetra (methy1enephosphonic acid) (PDTMP) is recommended as an alternative to¹⁶⁶Ho-DOTMP as there is very little accumulation in the kidney, liver or spleen, which is an important parameter for bone marrow ablation, as suggested from animal studies by Zolghadri et al. [38].

Fig. 1.(a) Schematic diagram of the basic structure of a nuclear research reactor and (b) an example of¹⁵²Sm(n,γ)¹⁵³Sm neutron activation reaction.

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A study by Cho et al. showed that¹⁶⁶Ho-chitosan complex used as a radiosynovectomy agent resulted in good clinical outcomes for the treatment of haemophilic arthropathy due to simpler and safer proto- cols which provide satisfactory and promising results without any seri- ous complication [39]. Observed on the target joints have shown excellent control of bleeding reducing the requirement for coagulation treatment [39]. The post-procedural biodistribution and pharmacoki- netic of¹⁶⁶Ho-chitosan complex for patient with knee synovitis can be evaluated using a gamma camera [40]. Due to the relatively short physical half-life, the¹⁶⁶Ho-chitosan complex has also been used for treating outpatients with skin cancer. Chung et al. reported that a study of 8 patients treated with¹⁶⁶Ho-chitosan patches showed excellent functional and cosmetic outcomes without any complications [41]. In addition, a pilot study that involved 22 patients with cystic brain tumour treated with ¹⁶⁶Ho-chitosan complex resulted in a radiological response of

70% and tumour control was prolonged in both low grade astrocytomas and benign tumours with clinical improvement [42]. Kim et al. also showed that a¹⁶⁶Ho-chitosan complex can be used for the treatment of renal cysts where 90% of the cysts regressed completely with no sig- niﬁcant complications [43].¹⁶⁶Ho-chitosan complex has also been used in patients with single and large HCC as reported by Sohn et al. in a phase II study that involved 54 patients [44]. This study showed remarkable results with a response rate of 78% and tolerable toxicities, for patients with tumour sizes of 3–5 cm.

166Ho-labeled poly-L-lactic acid (PLLA) microspheres have been used widely in Europe (Trade name QuiremSpheres®, Quirem, The Netherlands) for the treatment of liver malignancies. Following intra- arterial injection, the microspheres lodge in the microvasculature sur- rounding the tumour. Due to the average microsphere having a diame- ter of 30μm, the tumouricidal effects is maximised and the negative Table 1

List of medical radionuclides produced from stable targets by direct (n,γ) neutron activation [1,6,29].

Radionuclide Half-life, T1/2

Nuclear reaction

Decay product (stable)

Natural abundance (%)

Cross-section, σ(barns)

Energy of β⁻particles (keV)

Imaging γ-rays (keV)

Current clinical applications

Dysprosium-165 (¹⁶⁵Dy)

2.3 h ¹⁶⁴Dy (n,γ)¹⁶⁵Dy

Holmium-165 (¹⁶⁵Ho)

28.2 2650 1287

(83%) 1192 (15%)

94.7 (4%)

Relief pain in the synovial joints [164]

Erbium-169 (¹⁶⁹Er)

9.4 d ¹⁶⁸Er (n,γ)¹⁶⁹Er

Thulium-169 (¹⁶⁹Tm)

26.8 2.7 351(55%)

343 (45%) 110 (0.001%) 8 (0.2%)

Relief pain in the synovial joints [165,166]

Gold-198 (¹⁹⁸Au)

2.7 d ¹⁹⁷Au (n,γ)¹⁹⁸Au

Mercury-198 (¹⁹⁸Hg)

100 98.7 960 (99%)

285 (1%) 1088 (0.2%) 412 (96%) 676 (1%)

Therapy of bladder, cervix and prostate cancer, reduce ﬂuid accumulation secondary to a cancer, relief pain in the synovial joints [167–169]

Holmium-166 (¹⁶⁶Ho)

26.8 h ¹⁶⁵Ho (n,γ)¹⁶⁶Ho

Erbium-166 (¹⁶⁶Er)

100 64.7 1854

(50%) 1774 (49%)

81 (6%) Therapy and diagnosis of liver and skin cancer, head, neck and brain tumours, renal cysts, relief pain in synovial joints and bone cancer [151]

Lutetium-177 (¹⁷⁷Lu)

6.7 d ¹⁷⁶Lu (n,γ)¹⁷⁷Lu

Hafnium-177 (¹⁷⁷Hf)

2.6 2065 498 (79%)

385 (9%) 176 (12%)

208 (11%) 113 (6%)

Therapy and diagnosis of neuroendocrine and prostate cancer, relief pain from bone cancer [81,170]

Phosphorus-32 (³²P)

14.3 d ³¹P(n,γ)³²P Sulfur-32 (³²S) 100 0.18 1709 (100%)

Noγ-ray Therapy of polycythemia vera, essential thrombocythemia and leukemia, relief pain from bone cancer and in the synovial joints [111,171]

Rhenium-186 (¹⁸⁶Re)

3.7 d ¹⁸⁵Re (n,γ)¹⁸⁶Re

Osmium-186 (¹⁸⁶Os)^a

37.4 112 1069

(80%) 932 (22%) 581 (6%)

137 (9%) Relief pain from bone cancer [133]

Rhenium-188 (¹⁸⁸Re)

17.0 h ¹⁸⁷Re (n,γ)¹⁸⁸Re

Osmium-188 (¹⁸⁸Os)

62.6 76.4 2120

(71%) 1965 (26%)

155 (15%)

Therapy and diagnosis of liver and skin cancer, relief pain in synovial joints and bone cancer [122]

Samarium-153 (¹⁵³Sm)

46.3 h ¹⁵²Sm (n,γ)¹⁵³Sm

Europium-153 (¹⁵³Eu)

26.7 206 808 (18%)

705 (50%) 635 (32%)

103 (28%) 70 (5%)

Relief pain from bone cancer [134]

Tin-117 m (^117mSn)

13.6 d ¹¹⁶Sn (n,γ)^117mSn

Tin-177 m (^117mSn)

14.5 6 152 (26%)^b

129 (12%)^b 127 (65%)^b

159 (86%) 156 (2%)

Relief pain from bone cancer [172]

Strontium-89 (⁸⁹Sr)

50.5 d ⁸⁸Sr (n,γ)⁸⁹Sr

Yttrium-89 (⁸⁹Y)

82.6 0.058 1497

(100%)

Noγ-ray Relief pain from bone cancer [165]

Tantalum-182 (¹⁸²Ta)

114.4 d ¹⁸¹Ta (n,γ)¹⁸²Ta

Tungsten-182 (¹⁸²W)^a

100 20.5 524 (40%)

439 (21%) 260 (29%)

1231 (12%) 1189 (16%) 1121 (35%) 222 (8%) 100 (14%) 68 (41%)

Therapy of bladder cancer [173]

Thulium-170 (¹⁷⁰Tm)

128.6 d ¹⁶⁹Tm (n,γ)¹⁷⁰Tm

Ytterbium-170 (¹⁷⁰Yb)

100 105 968 (82%)

884 (18%)

84 (3%) Therapy of prostate cancer and relief pain from bone cancer [174,175]

Yttrium-90 (⁹⁰Y) 64.0 h ⁸⁹Y(n,γ)⁹⁰Y Zirconium-90 (⁹⁰Zr)

100 1.3 2282

(100%)

Noγ-ray Therapy of liver cancer and non-Hodgkin's lymphoma, relief pain in synovial joints [111,176,177]

a Decay product is not stable.

b Conversion electrons.

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effects on healthy liver parenchyma are reduced [34]. The¹⁶⁶Ho-labeled PLLA microspheres achieved sufﬁciently high activity of ~15 GBq de- pending on the neutron activation parameters which could result in a maximum speciﬁc activity of 450 Bq/microsphere [45]. The holmium embolization particles for arterial radiotherapy 1 study (HEPAR1)

showed that¹⁶⁶Ho radioembolization is practicable and safe for deliver- ing a dose of 60 Gy to the whole liver (this being known as the maximum tolerated dose). The distribution of the microspheres was visualized in-vivo by MRI or SPECT imaging post-administration [45,46]. A further study, HEPAR 2, showed that¹⁶⁶Ho microspheres in- Table 2

Summary of neutron-activated theranostics radionuclides which are commercially available or currently under clinical trials.

Radionuclide Maximum tissue range (mm) [31]

Radiopharmaceuticals (commercially available/under clinical trials)

Diseases References

166Ho 10.2 ¹⁶⁶Ho-chitosan complex HCC, skin cancer, cystic brain tumour, renal cysts, rheumatoid arthritis and hemophilic arthropathy

[36,37,39,42,44,51,53,151]

166Ho-DOTMP Bone metastases

166Ho-EDTMP

166Ho-PLLA microspheres Liver malignancies, head, and neck squamous cell carcinoma

177Lu 2.0 ¹⁷⁷Lu-DOTATATE Somatostatin receptor–positive gastroenteropancreatic

neuroendocrine tumours

[13,25,62,63,70,71,74,78,79,81,170]

177Lu-DOTMP Bone metastases

177Lu-EDTMP

177Lu-PSMA Metastatic castration-resistant prostate cancer (mCRPC)

186Re 4.5 ¹⁸⁶Re-HEDP Bone metastases [92,96,150,166]

186R-sulﬁde-colloid Rheumatoid arthritis

188Re 11.0 ¹⁸⁸Re-DMSA Bone metastases [115,120–122]

188Re-HEDP

188Re-HDD-iodized oil HCC

188Re-HDD-lipiodol

188Re-HSA microspheres

188Re-SCT Skin cancer

188Re‑tin-colloid Rheumatoid arthritis

153Sm 4.0 ¹⁵³Sm-EDTMP Bone metastases [134,140,178]

153Sm-HA Rheumatoid arthritis and haemophilic arthropathy

DMSA = dimercaptosuccinic acid; DOTATATE = dodecanetetraacetic acid coupled-tyr³-octreotate; DOTMP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethyl phosphonic acid;

EDTMP = ethylene diamine tetra(methylene phosphonate); HA = hydroxyapatite; HCC = hepatocellular carcinoma; HDD = 4-hexadecyl-1, 2, 9, 9-tetramethyl-4, 7-diaza-1,10- decanethiol; HEDP = 1-hydroxyethylene-1, 1-diphosphonic acid; HSA = human serum albumin; PLLA = poly(L-lactic acid); PSMA = prostate speciﬁc membrane antigen; SCT = skin cancer therapy.

Fig. 2.Clinical applications of currently available neutron-activated theranostics radiopharmaceuticals in different organs.

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duced a tumour response with an acceptable toxicity proﬁle, resulting in the effective treatment of liver metastases (73% of the patients showed control of disease after 3 months). In addition the use of SPECT/CT, demonstrated that personalized dosimetry could be performed with high precision [47]. Some recent studies [48–50] suggested that a tracer amount of¹⁶⁶Ho microspheres (± 250 MBq) can be used as a scout dose to optimize the therapeutic dose and select patients for advance treatment planning. This has been made commercially available as QuiremScout® (Quirem, The Netherlands) and has been proven safe in clinical settings as a better predictor of lung shunts and intrahepatic distribution than Technetium-99m macroaggregated albumin (^99mTc- MAA) which was originally developed for lung perfusion imaging [48–50]. Furthermore, a study by Bakker et al. showed that direct intratumoural injection of¹⁶⁶Ho-PLLA microspheres in three patients with head and neck squamous cell carcinoma (HNSCC) was a promising and negligibly invasive method of treatment [51].

Several studies have been carried out in the Netherlands using¹⁶⁶Ho microspheres. Surefire infusion system versus standard microcatheter use during ¹⁶⁶Ho radioembolization (SIM) is a study that explores whether the use of an anti-reflux catheter increases the tumour to non-tumour activity concentration ratio compared to a standard end- hole microcatheter [49,52]. The HEPAR PLUS study (HEPAR plus¹⁷⁷Lu- dodecanetetraacetic acid coupled-tyr³-octreotate (DOTATATE) in sal- vage neuroendocrine tumour patients) is another clinical trial that focuses on using an additional radiation boost on liver metastases to further decrease hepatic tumour burden as well as evaluating the safety of combine treatments, dosimetry, biodistribution, quality of life (QoL) and adverse events [53]. While the multicentre HEPAR primary phase II trial is to establish the safety and toxicity profile of ¹⁶⁶Ho radioembolization in unresectable advanced HCC patients, the study also includes efficacy, tumour marker response, QoL (through question- naires), biodistribution or dosimetry based on SPECT/CT as well as MRI and hepatobiliary scintigraphy for the assessment of hepatic function pre- and post-treatment [53,54]. In the HORA EST study (holmium radioembolization as adjuvant treatment to radiofrequency ablation for early stage HCC: a dose-finding study), patients with early stage HCC receive¹⁶⁶Ho radioembolization as adjuvant treatment after radiofrequency ablation. This is used to determine the therapeutic dose that will result in the delivery of a radiation-absorbed dose≥120 Gy to the target area in at least 90% of patients, toxicity profile, local tumour recur- rence and QoL [53,55].

4.2. Lutetium-177

The nuclear reactor product,¹⁷⁷Lu decays by emitting moderate en- ergyβ⁻particles (shorter tissue penetration range of 0.2–0.3 mm) and low-energy γ-rays which allows scintigraphy assessment of biodistribution and dosimetry [56]. Enriched¹⁷⁶Lu target can be used to produce high speciﬁc activity of¹⁷⁷Lu at 740 GBq/mg via neutron activation (¹⁷⁶Lu(n,γ)¹⁷⁷Lu) for the application of radiolabeled peptides and antibodies [57].¹⁷⁶Lu has the highest neutron activation cross- section of 2065 b compared to other currently used theranostic radionuclides in targeted therapy [6]. Therefore, production of large amounts of

177Lu can be easily achieved via neutron activation which is the most signiﬁcant advantage of this radionuclide [58]. The emission of low- energyγ-rays enables scintigraphy imaging of the biodistribution and allows personalized dosimetry before and during treatment [59,60]. As a moderate energyβ⁻emitter,¹⁷⁷Lu is more favorable than⁹⁰Y which is an energeticβ⁻emitter ideal for treatment of small tumours [60,61]

.¹⁷⁷Lu has a physical half-life of 6.7 d, which is comparable to¹³¹I with a half-life of 8 d. The relatively long half-life offers logistical advantage for supplying¹⁷⁷Lu to places that are far from the nuclear reactor with minimum loss due to radioactive decay [58]. Production of large amounts of¹⁷⁷Lu can be easily achieved, this being a signiﬁcant advantage for a radionuclide to be used for targeted therapy [58].

177Lu-prostate speciﬁc membrane antigen (PSMA) therapy employs a molecule that binds with high afﬁnity to PSMA a transmembrane pro- tein expressed in all types of prostatic tissue.¹⁷⁷Lu emitsβ⁻particles that can penetrate 1 mm in soft tissue, allowing effective delivery of radiation to tumour cells while sparing the nearby healthy tissues [62].

Currently only a few published trials that involved about 245 patients had been carried out using¹⁷⁷Lu-PSMA targeted therapy to treat metastatic castration resistant prostate cancer (mCRPC) and the outcomes have shown significant treatment response, well-tolerated and low- grade toxicities [24,63–68]. Thesefindings were supported by a study [62] showing that¹⁷⁷Lu-PSMA treatment had high response rates, low toxicities and lessen pain in men with mCRPC who have progressed after conventional therapies. A systematic review and meta-analysis by Yadav et al. also concluded that treatment for advanced stage mCRPC patients using¹⁷⁷Lu-PSMA had low toxicity profile as well as is an effective method for cases that does not response to standard treatments [69]. A recent prospective study on 14 patients by Aghdam et al. [70] in Iran showed the same results hence, treatment with

177Lu-PSMA can be considered the best options for end-stage mCRPC patients.Fig. 3shows an example of¹⁷⁷Lu-PSMA being an excellent theranostics radiopharmaceutical for the treatment of mCRPC. The co- emission ofγ-rays enables post-therapeutic imaging to monitor treatment response [63].

A phase II clinical trial carried out by Agarwal et al. showed that

177Lu-EDTMP is an effective and safe radiopharmaceutical for bone pain palliation in patients with metastatic prostate and breast carcinomas [71]. Another importantﬁnding from this study was that, no significant difference was found in toxicity or efﬁcacy for patients who received low-dose and high-dose of¹⁷⁷Lu-EDTMP [71]. In addition to the therapeutic usage, the of¹⁷⁷Lu-EDTMP at a dose of 185 MBq has been used as diagnostic agent where tumours were visibly indicated in the whole-body images post-administration. Furthermore, the post- therapy monitoring of the patients were accessible from the images obtained after 4 weeks post-injection of the therapeutic doses of¹⁷⁷Lu- EDTMP [72]. In an animal study using healthy mice, it was observed that 16% of¹⁷⁷Lu-DOTMP was uptake in skeletal muscle and almost all the remaining activity being eliminated through urine, thus causing less myelosuppression than¹⁵³Sm-EDTMP with an equivalent dose [73]. Chakraborty et al. [74] and Chang et al. [75] have both done a com- parison study between¹⁷⁷Lu-EDTMP and¹⁷⁷Lu-DOTMP using animal models. Both studies showed that¹⁷⁷Lu-EDTMP had marginally higher bone uptake and slower bone clearance than¹⁷⁷Lu-DOTMP and these radiopharmaceuticals were found to have great potential as bone pain palliation agents [74,75].

177Lu-DOTATATE is commercially available as Lutathera® (Ad- vanced Accelerator Applications SA, France, Paris) that had been widely used in many countries for the treatment of somatostatin receptor– positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) after it was approved by the United States (US) Food and Drug Admin- istration (FDA) in January 2018 [76,77]. From the phase 3 neuroendocrine tumours therapy (NETTER)-1 trial, patients with somatostatin receptor–positive midgut neuroendocrine tumours treated with¹⁷⁷Lu- DOTATATE showed markedly longer progression-free survival and a sig- niﬁcantly higher response rate than the patients treated with high-dose octreotide long-acting repeatable dose (control group) [14]. In nonrandomized trials,¹⁷⁷Lu-DOTATATE was found to be effective in treating patients with other gastrointestinal and pancreatic neuroendocrine tumours [78]. Patients who were active on a daily basis also experienced beneﬁts in functional health-related QoL [79]. The pre-therapy imaging of neuroendocrine tumours can be achieved using the whole- body scanning with¹⁷⁷Lu-DOTATATE. The image quality was found comparable to ¹¹¹In-octreotide and ⁶⁸Ga-dodecanetetraacetic acid coupled-tyr³-octreotide (⁶⁸Ga-DOTATOC) PET scans. In addition, dose estimation and treatment response monitoring after therapy to determine the dose delivery for the next fraction can be accurately calculated from the¹⁷⁷Lu-DOTATATE whole-body scans [80].

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Interest in the further development of¹⁷⁷Lu-based radiopharmaceuticals has been growing over the last decade due to the high theranostic potential and convenient production logistics of this radionuclide [74,81–86]. There has been an increasing number of published studies on the in vivo and in vitro applications of improved and new¹⁷⁷Lu- labeled compounds [34]. Hence,¹⁷⁷Lu is undeniably an extremely valu- able reactor produced radionuclide for theranostic applications and the usage is predicted to increase further in the future [81].

4.3. Rhenium-186

186Re is produced via¹⁸⁵Re(n,γ)¹⁸⁶Re reaction with¹⁸⁵Re having a neutron cross-section of 112 b and isotope abundance of 37.4% [6]. It has an averageβ⁻energy of 0.35 MeV andγ-rays energy of 137 keV that is suitable for imaging purposes [31]. The meanβ⁻particle ranges in soft-tissue and bone are 1.1 and 0.5 mm, respectively [87].¹⁸⁶Re can also be produced in a cyclotron by a (p,n) reaction on¹⁸⁶W. However, production of high purity¹⁸⁶Re can be achieved in large quantities at lower cost using nuclear reactors [6]. Neutron activation of natural rhenium target will produce both¹⁸⁶Re and¹⁸⁸Re, as¹⁸⁵Re (37.4%,σ= 112 b) and¹⁸⁷Re (62.6%,σ= 72 b) are both present in natural rhenium. The percentage of each radionuclide produced relies on the irradiation and post-irradiation period (cooling time) because¹⁸⁸Re (T1/2= 17.01 h) has a physical half-life much lower than¹⁸⁶Re (T1/2= 3.72 d). Hence, longer irradiation and cooling time will produce more¹⁸⁶Re and fewer

188Re, but the specific activity is low. The proportion of¹⁸⁸Re can be made to be less than 5% by irradiating the target for more than 7 d and a cooling period of 4 d [6]. Although the specific activity is low when using natural rhenium target (e.g. 1.3 GBq/mg from thermal neutronflux of 3 × 10¹³n/cm²/s irradiated for 7 d [88]), it is adequate for bone pain palliation and radiosynovectomy but may not be sufficiently high enough for clinical antibody and peptide radiolabelings [6]. While enriched¹⁸⁵Re will provide a higher specific activity of 18.5 GBq/mg for an irradiation period of 2 d with thermal neutronflux of 10¹⁴n/

cm²/s [89].

186Re-sulfide-colloid is an effective treatment for inflammatory joint diseases such as rheumatoid arthritis and synovial joints [90].¹⁸⁶Re-sulfide-colloid is routinely applied for cases involving middle sized joints where good to excellent results are reported in 50–60% of the cases, in ankle, elbow, hand, hip and shoulder joints. Another study reported good to very good results in 83% of elbow joints [91]. In Europe,¹⁸⁶Re- sulfide-colloid has been used for more than 25 years in Europe due to its effectiveness in rheumatoid arthritis whereby its adverse effects are negligible and intermittent [92–94]. The dosimetry assessment post- administration can be performed using the external imaging with gamma camera or SPECT/CT [95].

As a surface bone-seeking agent,¹⁸⁶Re-1-hydroxyethylene-1, 1- diphosphonic acid (HEDP) has been popular for bone palliative treatments. The recommended amount of activity for bone metastases is 1285 MBq and the maximum tolerable dose is considered to be 2960 MBq from data originating from prostate and breast cancer patients [96–100]. Following intravenous administration, the peak uptake of¹⁸⁶Re-HEDP in skeletal bone can be seen within 3 h [101,102]. The low energyγ-rays, which is similar toγ-ray energy (140 keV) of the most commonly used^99mTc diagnostic radionuclide, has enables SPECT imaging to estimate the radiation dose delivered to the bone metastatic sites [89,95]. Studies showed that overall pain relief was seen in 80% of hor- mone refractory prostate cancer patients after treatment using 1285 MBq of¹⁸⁶Re-HEDP with an average period of 7 weeks [97,103].

It was also reported that after administration of a single dose of¹⁸⁶Re- HEDP, signs of improvement were seen in 80–90% patient, which typi- cally occur between 24 and 48 h. The efﬁcacy of¹⁸⁶Re-HEDP has been proven in placebo-controlled, randomized studies [97,104]. An average of 26 Gy absorbed dose in bone metastases and 1.73 Gy in red marrow were reported when using the standard activity of 1285 MBq [97]. A high therapeutic index was observed with a mean ratio of tumour to marrow dose of 34:1 (mean value) [103]. In addition, the radioactivity was cleared in the urine and blood rapidly. Toxicity was limited to tem- porary myelosuppression, with platelet and neutrophil nadir at 4 weeks after therapy, and the treatment was generally completed in 8 weeks, marked by patient's recovery [105].

Fig. 3.Clinical example of¹⁷⁷Lu-PSMA theranostics treatment for mCRPC. (a) Pre-treatment PET/CT scan was done using⁶⁸Ga-PSMA11. (b) Co-emission ofγ-rays from¹⁷⁷Lu enables gamma imaging during therapy to monitor treatment response. (c)^99mTc-PSMA scintigraphy was done as follow-up imaging after the¹⁷⁷Lu-PSMA treatment. GM = geometric mean;

MIP = maximum-intensity projections; p.i. = post-injection. (Reproduced with permission from [63]).

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4.4. Rhenium-188

188Re has an averageβ⁻energy of 0.76 MeV associated with 155 keV ofγ-rays and a relatively short physical half-life of 17.0 h [31]. The maximum tissue penetration range of its beta particle is about 10 mm and the mean range is 3.5 mm [106]. By using a highly enriched¹⁸⁷Re target,¹⁸⁸Re can be produced in a reactor via¹⁸⁷Re(n,γ)¹⁸⁸Re with neutron cross- section of 76.4 b. Speciﬁc activity of 22.2 GBq/mg can be achieved from 2 h irradiation in a thermal neutronﬂux of 10¹⁴n/cm²/s [89]. Similar to

186Re, large amounts of¹⁸⁸Re can be produced via neutron activation that are appropriate for medical applications such as treatment of HCC, bone pain palliation and radiosynovectomy [6]. One of the limitations of

188Re is its short physical half-life which causes logistic challenge for transportation to locations which are far away from the reactor [58].

Hence, the¹⁸⁸W/¹⁸⁸Re alumina-based generator has been developed to solve this problem [89].¹⁸⁸W has a physical half-life of 69.4d and it can be produced in a nuclear reactor with thermal and high energy neutrons by irradiation of tungsten oxide of 96.07% enrichment in¹⁸⁸W [107].

The use of¹⁸⁸Re‑tin-colloid in radiosynovectomy is particularly bene- ficial for treating large joints due to its high energeticβ⁻particles [108]. In a study by Shukla et al.,¹⁸⁸Re‑tin-colloids microparticles showed greater retention as there was no leakage from the side of the knee joints and patients received good therapeutic outcomes with lower whole-body absorbed dose [109]. Shamim et al. further confirmed that¹⁸⁸Re‑tin-colloid in radiosynovectomy is an effective treatment for patients with chronic inflammatory knee joint conditions, where a significant decline in pain scores were observed at 3, 6 and 12 months [110]. The authors also suggested that ideal candidates for this treatment are those with tiny or no swelling, shorter duration of disease, slight tenderness, ability to move, and normal/minor radiographicfinding. A multicenter study that compared the therapeutic efficacy between⁹⁰Y, ³²P and ¹⁸⁸Re radiocolloids on 99 rheumatoid arthritis patients revealed that most patients experienced pain relief at 1-month follow-up, achieved greater improvement after 3 months and persisted up to 12 months [111]. The pain relief score (based on a 10-step visual analogue scale) between these three radiocolloids did not differ significantly from each other (p > 0.10). The distribution of the administered¹⁸⁸Re‑tin-colloid and leaking of the radioactivity post-administration at different time points can be studied using gamma camera [112].

The reason of rapid symptom response after¹⁸⁸Re administration is due to its highβ⁻particles energies and short physical half-life. Exten- sion of response interval and progression free survival are observed in fractionated bone palliative treatment. A study by Palmedo et al. in prostate cancer patients treated with¹⁸⁸Re-HEDP for osseous metastases showed low toxicity with moderate leukopenia and thrombopenia [106]. It was also reported that repeated¹⁸⁸Re-HEDP therapies were more effective than single dose therapies for pain palliation, having obtained a response rate of 92% and time of response was 5.66 months.

Liepe et al. found no indication of either systemic or local intolerance to¹⁸⁸Re-HEDP therapy, however 16% of patients had aflare reaction with an increase in pain within 14 d after treatment [111]. Biersack et al. also documented a positive outcome of repeated therapy on overall survival with the highest mean survival rate of 15.7 months after the ini- tial therapy. It was reported that all patients had bone pain with more thanfive lesions [113]. Nevertheless, Lange et al. reported that single injection and repeated therapy of¹⁸⁸Re-HEDP had similar pain response with an overall QoL response rate of 68% [114]. A recent study by Shinto et al. that investigated patients with painful bone metastases due to bladder, breast, lung, prostate and renal cancers, treated with¹⁸⁸Re- HEDP showed that 90% of them experienced relief from bone pain [115]. It has been evident that¹⁸⁸Re-HEDP showed clinical benefits and can be practiced in routine clinics due to its low toxicity and adverse effects, and the outcome is equivalent to external beam radiotherapy.

188Re-dimercaptosuccinic acid (DMSA) has also been utilized for bone metastases originate from breast and prostate cancers, whereby this radionuclide biodistribution is similar to^99mTc analogue. The uptakes by

normal bone and nearby healthy tissues are low, with signiﬁcantly high uptake in bone metastases and kidney [116].

188Re-4-hexadecyl-1, 2, 9, 9-tetramethyl-4, 7-diaza-1,10-decanethiol (HDD)-lipiodol has been used for HCC treatment [117]. This radiopharmaceutical was administered intraarterially to the liver via femoral and hepatic artery [118].¹⁸⁸Re has a number of advantages over¹³¹I, due to its lowerβ⁻energy emission, shorter physical half-life, on-site generator availability and low toxicity. Treatment with¹⁸⁸Re-HDD-lipiodol is a simpler process when compared to⁹⁰Y microspheres and is suitable for the majority of referred patients diagnosed with HCC [107]. In an impressive multination study of 185 patients sponsored by the IAEA, it was documented that the overall tolerance of intra-arterial¹⁸⁸Re-HDD-lipiodol treatment for inoperable HCC was outstanding, resulting in three com- plete responses and 19 partial responses with 1- and 2-year survival rates of 46% and 23%, respectively [119]. The low gamma energy (155 keV, 15%) emission from¹⁸⁸Re is ideal for pre-treatment imaging using a scout dose (~150 MBq) to determine the maximum tolerated dose to the bone marrow, lungs and normal liver as well as to calculate the desired therapeutic radioactivity to the tumour [119]. Liepe et al. reported that patients with colorectal liver metastases or HCC treated using

188Re-human serum albumin (HSA) microspheres with high activity above 10 GBq was well tolerated in 30% of patients and it was concluded that patients should obtain earlier and repetitive therapy to improve treatment efﬁcacy [120]. In a study by Kumar et al., 93 patients were administered with 185 MBq of¹⁸⁸Re-HDD-iodized oil via hepatic artery and this resulted in tumour response rates of 100%, 95%, 90%, 58% and 30% between patients with survival rates at 6, 9, 12, 24 and 36 months respectively, with a median survival of 980 d [121].

188Re is also ideal for targeted therapy of superﬁcial skin cancers, such as non-melanoma skin cancer, due to the short penetration range of itsβ⁻ particles. Currently,¹⁸⁸Re-skin cancer therapy (SCT) epidermal radioiso- tope is commercially available by OncoBeta® GmbH, Germany where it is regularly applied for the treatment of basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) [122]. A recent study by Cipriani et al.

showed a remarkable result of 36 patients (24 BCC and 12 SCC) success- fully treated with only one session of¹⁸⁸Re-SCT and no side effects were observed [123].

4.5. Samarium-153

Neutron activation of stable¹⁵²Sm will result in the production of

153Sm, a beta emitter that also emitsγ-rays at a physical half-life of 46.3 h [136].¹⁵³Sm emits mediumβ⁻energies with an average of 0.23 MeV [31] and the mean penetration range in soft tissue is 0.8 mm [56]. In addition, it emitsγ-radiation at the energy of 103 keV, which is well suited for gamma imaging using a low energy collimator. The images with high spatial resolution and low noise can be acquired after every treatment which can be utilized for evaluation of radioactive leakage to other organs [95]. A large quantity of high speciﬁc activity¹⁵³Sm can be produced via¹⁵²Sm(n,γ)¹⁵³Sm reaction due to the high thermal neutron capture cross-section of 206 b. The speciﬁc activity is high enough for bone palliation and radiosynovectomy treatments [6,58].

Sometimes enriched form of¹⁵²Sm target is used to produce¹⁵³Sm with even higher speciﬁc activity for targeted radionuclide therapy [58]. In a study reported by Ramamoorthy et al. [124], speciﬁc activity of 11 GBq/mg and 44 GBq/mg were obtained using natural¹⁵²Sm and enriched¹⁵²Sm, respectively. Being a low-cost nuclear reactor product,

153Sm possess many beneﬁts for theranostic cancer management. The imaging capability of¹⁵³Sm enables baseline imaging and restaging scans using the same radiopharmaceutical formulation but with lower activity to enhance efﬁcacy and safety of the overall treatment.

153Sm has been an excellent radionuclide for bone pain palliation since¹⁵³Sm-EDTMP (Quadramet®, Lantheus Medical Imaging, Inc., USA) was approved by the US FDA in 1997 [6]. The recommended dose of¹⁵³Sm-EDTMP of 37 MBq/kg [125] resulted in pain reduction in 55–70% of evaluated patients [126,127]. Quadramet® is mainly

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utilized to treat the pain associated with osteoblastic and mixed bone metastases, which are conﬁrmed on a radionuclide bone scan, and has reported efﬁcient in patients with breast, prostate and other primary cancers [128–130]. Bone metastases happens in more than 50% of different cancer types and has 80% possibility of being very painful in breast, lung and prostate cancer patients. Therefore, this treatment is highly favorable for a wide group of patients in reducing bone pain [34].¹⁵³Sm has several advantages over⁸⁹Sr due to its lower beta energy, shorter physical half-life, faster radiation delivery, rapid clearance from the body and relatively lower myelotoxicity [6,131,132]. Pain relief by

153Sm-EDTMP generally starts after 2–7 d post-administration and can retain for as long as 2–17 weeks [127,133]. Mild myelotoxicity may hap- pen with approximately 10–40% decrease in platelet and leukocyte counts, but full recovery is expected within 6–8 weeks [127].

Kolesnikov-Gauthier et al. reported that an effective and helpful treatment (besides improving QoL) in patients who suffer from bone metastases^,particularly with breast or prostate cancer, is ¹⁵³Sm-EDTMP therapy [134]. Evaluation of biodistribution and dosimetry estimation of¹⁵³Sm-EDTMP at 24 h post-administration can be performed using a gamma camera or SPECT/CT scanner with low energy, high-resolution collimators. The images were found similar to the commonly used

99mTc-methylenediphosphonate (MDP) bone scan [135–137]. In a recent study, Taheri et al. reported that¹⁵³Sm-EDTMP and¹⁷⁷Lu-EDTMP achieved similar safety and effectiveness in pain palliation treatment of skeletal metastases, whereby signiﬁcant reduction in pain levels were observed after 2 weeks for both treatment groups, and continuing to last for 12 weeks after treatment [138]. Elzahry et al. mentioned that a single therapeutic dose of¹⁵³Sm-EDTMP offers an effective and safe option for patients with painful bone disseminations, in which 67% of the patients showed overall therapeutic bone regression/stabilization and 33% showed bone progression [139].

153Sm can also be utilized for radiosynovectomy or radiosynoviorthesis of intermediate size joints (ankles and elbows) [6]

. For example,¹⁵³Sm-hydroxyapatite (HA) has been used in the treatment of haemophilic arthropathy and the treatment is proven to be effective, safe and affordable. By injecting higher dose of ¹⁵³Sm-HA, radionecrosis effect can be improved due to the optimum penetration range of the medium energy beta radiations [140]. Calegaro et al. studied the effectiveness of¹⁵³Sm-HA in the treatment of hemophilic arthropathy in ankles and elbows [140]. The study showed an observed substantial improvement in both ankles and elbows following¹⁵³Sm- HA radiosynovectomy, in which the grade of pain relief measured was greater for ankles (improvement of 71% and 61%) than elbows (improvement of 46% and 37%), after 12 and 42 months, respectively. The distribution of ¹⁵³Sm-HA and incident of joint effusion at different time points post-administration has been performed using gamma camera scans. The results obtained from this study corresponded with those reported in the previous literatures [141,142]. Calegaro et al. also de- scribed the¹⁵³Sm-HA treatment as cost-effective, minimally invasive and highly safe in managing pain and bleeding [140].

In an experimental study carried out by Hashikin et al.,¹⁵³Sm-labeled ion-exchange resin microparticles (Amberlite® IR120, Rohm and Haas Company, USA) demonstrated superior characteristics compared to other radionuclides for potential use in hepatic radioembolization [143].

However, a comprehensive dosimetry studies to estimate total¹⁵³Sm activity to deliver equivalent tumour dose from commercially available 3 GBq⁹⁰Y microspheres, as well as animal studies for in-vivo distributions and biochemical stability prior to clinical studies are needed.

5. Recent developments of neutron-activated theranostics radionuclides for clinical applications

5.1. Gastroenteropancreatic neuroendocrine tumors

GEP-NETs are among the most complicated tumours to detect and treat owing to their speciﬁc properties, thus patient' survival is highly

reliant on histology and stage [144]. Among all the theranostic radionuclides,¹⁷⁷Lu has become the most widely used radionuclide in the last decade for the treatment of somatostatin receptor-positive GEP-NETs.

In 2018,¹⁷⁷Lu-oxodotreotide has been approved in Europe for the treatment of GEP-NETs as an alternative therapy opportunity [146]. IAEA has also been supporting the development of low cost and easily available

177Lu-labeled antibodies and peptides for the treatment of other primary cancers such as prostate, liver, mCRPC, etc.¹⁷⁷Lu has low toxicity, promising anti-tumour activity and improves QoL in patient, hence, the clinical application of¹⁷⁷Lu is expected to continue to grow in the com- ing decade for a wide range of targeted radionuclide therapies.

5.2. Bone metastasis

Bone metastasis is the advanced stage of various cancers and it causes variable symptoms such as severe pain, pathologic fractures, hy- percalcemia and metastatic spinal cord compression [147]. Bone metastasis requires treatment that can relief pain in patient and eventually improving the QoL. In bone pain palliative treatment, radionuclides pro- ducingβ⁻particles with high energy are essential for the therapy, it would be beneﬁcial however if the associatedγ-rays were of low energy for diagnostic imaging. Thus,¹⁵³Sm and⁸⁹Sr are the most suitable candidates for this option since³²P is no longer used due to its severe bone marrow toxicity [148,149].¹⁵³Sm has more advantages than⁸⁹Sr as it also emitsγ-rays that is useful for imaging. Meanwhile,¹⁷⁷Lu,

186Re and¹⁸⁸Re were found to be as efficient and safe as¹⁵³Sm for bone palliative treatments. Other features such as capability to produce in high specific activity, suitable half-life, minimum radioactivity to the bone marrow, sufficientβ⁻particles energy for therapeutic andγ-rays energy for diagnostic as well as provide an extensive outcome with a single administration are taken into consideration for this procedure [147].

5.3. Radiosynovectomy

Radiosynovectomy has been applied as an option minimally invasive local treatment for refractory joint inﬂammations or complications. It uses ionizing radiation to irradiate the inﬂamed synovial membrane by intra-articular injection of the unsealedβ⁻emitting radionuclide coupled with a suitable particle or colloid [95]. Radiosynovectomy for the treatment of joint pain caused by arthropathies currently utilizes

186Re and⁹⁰Y, as both radionuclides are commercially available in the colloidal form [150]. This treatment is easy to perform, cost-effective, re- liable and it does not cause any adverse effects, as documented so far.

Both radionuclides are applied to different types of joints;¹⁸⁶Re is suitable for ankle, elbow, hip, shoulder, subtalar and wrist joints, while⁹⁰Y is suitable for the knee joint only. Studies using¹⁶⁶Ho (on ankle, elbow and knee joints) [39],¹⁵³Sm (ankle and elbow joints) [140] and¹⁸⁸Re (knee joint) [110] have been carried out and promising results such as signiﬁcant pain relief have been observed. Some researchers have been exploring new formulations for radiosynovectomy, such as

166Ho-labeled ferric hydroxide macroaggregates (FHMA) complex, chitosan complex, PLLA-microspheres and PLLA-macroaggregates. Results to date show that these formulations have good retention on the administration site and no signiﬁcant leakage of radionuclides was observed in animal studies [151]. Eventually, other radionuclides can also be labeled with these formulations for similar applications in the future.

5.4. Head and neck cancer

Patients with locoregional recurrences of HNSCC have limited treatment choices, hence a single session, relatively safe and minimally invasive procedure has been preferred for palliative management of this disease [51]. For treating small tumours in the HNSCC and cystic brain tumour, direct intratumoural injection can be used as a minimally invasive and targeted therapy whereby the radionuclide is injected directly