Yttrium-90 and Rhenium-188 Radiopharmaceuticals for Radionuclide Therapy

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During this CRP, several groups dealt with the measurement of 90 Sr content in 90 Y samples using the following analytical methodologies: (a) (b) (c) (d) (e) (f) EPC (Brazil, Cuba, India, Serbia, Syrian Arab Republic, Thailand, Viet Nam); Extraction resin chromatography (Sr-Spec, DGA) (Poland, Syria); Cation exchange paper chromatography (Wh P81) (Poland); Measurement of the half-life of 90 Y with a β counter after allowing complete decay of 90 Y (Brazil, Cuba, Syrian Arab Republic); Inductively coupled plasma optical emission spectroscopy (ICP OES) (Brazil, Thailand); Inductively coupled plasma mass spectroscopy (ICP MS) (Syrian Arab Republic). Work carried out by the groups in India and Thailand aimed at validating the EPC technology using, in particular, procedures described in the United States Pharmacopeia to validate their results. This method proved to be reliable and reproducible. Owing to limited access to key reagents needed for EPC, several participants investigated alternative solvents and solid supports that allowed for the achievement of good results. Hence, it is expected that the EPC method will prove to be very effective and will be widely applicable in Member States. The extraction resin chromatographic method was validated in Poland, and a lowest detection limit (DL) of 3 × 10 –6 % of 90 Sr was achieved in a sample containing 250 MBq of 90 Y. A previously recommended method for indirectly assessing the presence of metallic impurities in 90 Y eluates rested on the analysis of results of the 90 Y labelling of the peptide 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (Tyr 3 ) octreotate (DOTATATE). High labelling yields associated with high specific activity provided robust evidence for a very low content of non-radioactive metals. Further validation studies carried out during the CRP strongly confirmed that this easy to use method constitutes a sensitive tool for qualitative assessment of the metallic purity of 90 Y eluates. 1.3.3. Yttrium-90 labelled antibodies Labelling of various antibodies (rituximab, ERIC1, hR3) with 90 Y has been studied using 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (DOTA) and diethylenetetraminopenta acetic acid (DTPA) as chelating systems for the radiometal. Preliminary work was carried out on the characterization of the antibody after tethering the chelating group to its structure. This involved determination of the number of chelating groups per antibody molecule and 4
etention of the antibody’s target specificity. After labelling, the stability of the resulting conjugate was tested both in vitro and in vivo, and its affinity for the target tissue, tumour accumulation and potential therapeutic efficacy were evaluated using experimental animal models. Standard procedures employed for this characterization were optimized and implemented by various research groups. In particular, the research groups in Cuba, Germany, India, Poland, the Syrian Arab Republic and Viet Nam, optimized the conjugation of the chelating system to the commercially available antibody rituximab using the bifunctional ligands 2-(4-isothiocyanatobenzyl) 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (p-SCN-Bn-DOTA), DOTA N-hydroxy succinimidyl (NHS) and DTPA. The group in Germany labelled the antibody ERIC1 with 90 Y as a potential candidate for the treatment of neuroblastoma and small cell lung cancer. Labelled ERIC1 was tested in animal models bearing neuroblastoma tumours. Biodistribution data showed high tumour accumulation and reproducible dose dependent tumour response. The optimal dose for complete tumour regression was found to correspond to 2 MBq/animal. The groups in Cuba, India and the Syrian Arab Republic presented preliminary results on labelling of the antibody hR3. Based on extensive experience in the field of antibody labelling, the group in Cuba also provided various protocols that included purification and quality control steps. 1.3.4. Yttrium-90 biotin pretargeting The aim of this subproject was to demonstrate the advantages of the pretargeting approach when labelled antibodies are employed in cancer therapy. Preliminary work on this subject was performed to optimize the so-called three step pretargeting protocol based on the avidin biotin system in terms of the most appropriate concentration and time of administration of the various reagents. The group in Italy conducted a preclinical evaluation of a new biotin DOTA conjugate labelled with 90 Y. Interestingly, the labelling was carried out using an automatic synthesis module, which afforded the final radiopharmaceutical in high radiochemical purity (RCP) and under sterile and pyrogen free conditions. A remarkable result was reported by the group in Germany, which revealed that isolated tumour cells accumulated 20-fold higher radioactivity when a biotinylated antibody was employed as compared to a control using a non-biotinylated antibody. This group also performed extensive in vivo studies in tumour bearing mice, showing that the pretargeting approach is a promising technique to deliver high doses to the tumour with reduced side effects. Various additional parameters of this approach could still be finely tuned to optimize tumour to background ratios. 5
Page 1 and 2: IAEA RADIOISOTOPES AND RADIOPHARMAC
Page 3 and 4: YTTRIUM-90 AND RHENIUM-188 RADIOPHA
Page 5 and 6: IAEA RADIOISOTOPES AND RADIOPHARMAC
Page 7 and 8: FOREWORD The IAEA helps to promote
Page 9 and 10: CONTENTS CHAPTER 1. INTRODUCTION ..
Page 11 and 12: 7.4. Discussion ...................
Page 13 and 14: CHAPTER 12. DEVELOPMENT OF 90 Sr/ 9
Page 15 and 16: Chapter 1 INTRODUCTION 1.1. BACKGRO
Page 17: devices were designed to improve th
Page 21 and 22: Binding affinity of these derivativ
Page 23 and 24: Chapter 2 FUNDAMENTAL CONCEPTS IN R
Page 25 and 26: A special characteristic of radioph
Page 27 and 28: β particles emitted by 90 Y. Numer
Page 29 and 30: 2.3.1. Exploitation of certain meta
Page 31 and 32: 2.3.3. Antibodies The high specific
Page 33 and 34: cell cultures, presents one example
Page 35 and 36: Another very promising form of radi
Page 37 and 38: destructive processes within the jo
Page 39 and 40: esearch efforts, since then. Howeve
Page 41 and 42: [2.18] HAMILTON, J.G., The metaboli
Page 43 and 44: [2.52] GOLDENBERG, D.M., et al., Mu
Page 45 and 46: Chapter 3 DEVELOPMENT OF RADIOPHARM
Page 47 and 48: FIG. 3.3. Elution efficiencies for
Page 49 and 50: FIG. 3.5. Electrodeposition of yttr
Page 51 and 52: The results of the experiments of r
Page 53 and 54: TABLE 3.3. RESULTS FOR 90 Sr/ 90 Y
Page 55 and 56: FIG. 3.11. Elution yield of a 90 Sr
Page 57 and 58: According to Fig. 3.12, there is a
Page 59 and 60: eagent (Sigma). The mean recovery o
Page 61 and 62: FIG. 3.18. Variation of RCP (%) of
Page 63 and 64: (20 and 30 min) and volume of 188 R
Page 65 and 66: FIG. 3.24. Variation of labelling y
Page 67 and 68: (c) Clodronate: 20 mg of clodronate
Page 69 and 70:
Chapter 4 EVALUATION OF THE 90 Sr/
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Kamadhenu consists of five main com
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Quality control of radiolabelling w
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The electrochemical deposition of 9
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FIG. 4.5. Typical pattern of the wh
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FIG. 4.6. Elution profile from the
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FIG. 4.8. CD20 recognition in Ramos
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4.5. RECOMMENDATIONS AND FUTURE WOR
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adioiodine labelled anti-NCAM antib
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FIG. 5.1. Comparison of biodistribu
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FIG. 5.3. Three step strategy. Biot
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TABLE 5.1. THREE STEP PRETARGETING:
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5.1.4. Therapeutic experiments with
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5.1.4.4. Conclusion The radioiodine
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control procedure for detection of
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6.1.3. Recovery of doped 85/89 Sr 2
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6.2. PREPARATION AND BIOEVALUATION
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(a) (b) (c) FIG. 6.5. PD-10 column
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FIG. 6.7. SDS PAGE pattern of ritux
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FIG. 6.10. HPLC pattern of pure 90
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FIG. 6.13. Cell binding studies wit
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6.2.1.6. Conclusion The procedure f
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FIG. 6.17. Elution profile of 90 Y
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form NADH, which, in turn, causes t
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FIG. 6.19. In vivo distribution pat
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ACKNOWLEDGEMENTS The authors of thi
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Chapter 7 DEVELOPMENT OF THERAPEUTI
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the residual breast tissue becoming
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7.2.5.2. Automatic procedure The la
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FIG. 7.2. RCP values of 90 Y r-BHD
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FIG. 7.3. Pyrogen test shows result
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to avidin at the 1:4 avidin:r-BHD m
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[7.9] SU, F.M., GUSTAVSON, L.M., AX
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8.1. INTRODUCTION In past years, th
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(a) FIG. 8.1. (a) Schematic illustr
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Preliminary synthesis of the biotin
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(a) (b) FIG. 8.4. (a) PEGylated and
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TABLE 8.2. BIODISTRIBUTION IN RATS
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A specific binding to avidin was ev
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[8.13] BOSCHI, A., DUATTI, A., UCCE
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90 Y solution obtained from a 90 Sr
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From each fraction, a ~1 g aliquot
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FIG. 9.2. Relationship between 90 S
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with 188 Re obtained from the 188 W
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9.3.2. Labelling of DPA ale DPA ale
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FIG. 9.8. TLC radiochromatogram of
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(-) 188 Re(CO) 3 (+) (-) 99m Tc(CO)
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the HSA solution containing sodium
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TABLE 9.3. RESULTS OF 99m Tc LABELL
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9.4.4. Yttrium-90 and 177 Lu labell
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FIG. 9.14. In vitro stability of 90
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(a) (b) (c) (d) (e) (f) (g) (h) (i)
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TABLE 9.8. YTTRIUM-90 CITRATE COLLO
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(a) (b) FIG. 9.17. Grain size distr
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TABLE 9.10. BIODISTRIBUTION AFTER A
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FIG. 9.19. Structure of DOTA biotin
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[9.8] WESTERA, G., GADZE, A., HORST
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Chapter 10 DEVELOPMENT, PREPARATION
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acidic pH) and the vial heated for
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10.2.2.1. Materials and methods (a)
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Using a semiquantitative method, th
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FIG. 10.3. Whole body, SPECT and ta
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TABLE 10.4. ORGAN DISTRIBUTION STUD
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was assessed by measuring the relea
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—— Biological studies: The whol
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or liver) (see Fig. 10.7). The resu
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(b) Results and discussion Healthy
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and the pellet (particles of HA lab
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FIG. 10.11. Organ distribution stud
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The procedure was as follows: —
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TABLE 10.5. INFLUENCE OF CHEMICAL I
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analysed using ICP OES was within t
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suggested for separation of pure 86
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adionuclidic purity of the 90 Y sol
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FIG. 10.16. (a) Strontium-90/yttriu
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[10.5] DJOKIĆ, D.J., JANKOVIĆ, D.
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Yttrium-90 is one of the radionucli
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(a) (b) (c) The generator was prepa
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—— Development of EPC: The EPC
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FIG. 11.4. Elution curve of 90 Sr e
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11.4. YTTRIUM-90 MAbs The use of th
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FIG. 11.6. RCP measured using ITLC
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FIG. 11.9. Biodistribution of 90 Y
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11.5. YTTRIUM-90 EDTMP Bone metasta
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FIG. 11.14. Electrophoresis of 90 Y
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FIG. 11.15. Particle size distribut
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11.7. CONCLUSION During this CRP, a
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Chapter 12 DEVELOPMENT OF 90 Sr/ 90
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12.1.1.4. Acid vapour trap and radi
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12.1.8. Yttrium-90 peptide labellin
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(a) FIG. 12.3. Yttrium-90 elution p
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FIG. 12.6. HPLC of 90 Y DOTATATE. 1
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Chapter 13 BIFUNCTIONAL BISPHOSPHON
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latter requirement [13.10]. When th
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whether the organometallic core sel
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The fate of a targeted imaging prob
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FIG. 13.7. SPECT/CT images showing
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FIG. 13.9. TLC SG analyses of [ 188
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FIG. 13.11. Stability study (toward
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Ex vivo biodistribution studies at
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was in the form of either pertechne
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FIG. 13.19. Absolute uptake of 99m
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[13.2] ZHANG, S., GANGAL, G., ULUDA
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[13.31] DE ROSALES, R.T.M., et al.,
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The activity due to 90 Sr should be
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14.3.1.2. Operation of the 90 Sr/ 9
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antibody were taken, to which 90 Y
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operation, radiopharmaceutical grad
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14.4.1.3. Operation of the stage II
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A typical EPC pattern for a 90 Y pr
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FIG. 14.10. Decay curve of carrier
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FIG. 14.12. ITLC of 90 Y rituximab.
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FIG. 14.13. Reaction scheme for lab
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TABLE 14.6. STABILITY (%) OF 90 Y D
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FIG. 14.18. Microsphere albumin siz
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[14.3] PANDEY, U., DHAMI, P.S., JAG
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naphthalene and 1.2 g of 2,5-diphen
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A-2.2. Materials The method for sep
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out using a Wallac 1411 spectromete
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A-5.3. Procedure The technique was
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Although acyclic chelators offer ma
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(b) (c) and 90 Y colloids, both ser
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CONTRIBUTORS TO DRAFTING AND REVIEW
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INDIA Allied Publishers 1 st Floor,
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A key requirement for the effective
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Yttrium-90 and Rhenium-188 Radiopharmaceuticals for Radionuclide Therapy

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