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Home , Alpha decay, Beta particle, Cluster decay, Decay energy, Double electron capture, Electron capture

Physics of Novel Modalities:

James S. Welsh Stritch School of Medicine Loyola University Chicago Disclosure

• Member of the Advisory Committee on the Medical Uses of (ACMUI) for the United States Nuclear Regulatory Commission (NRC) • Board of directors: – Coqui Radioisotopes – Colossal Fossils Learning Objectives

• Understand the basic physics of alpha, beta, and other types of radioactivity • Gain some familiarity with the various sealed and unsealed radionuclides commonly used in radiation oncology

Types of radioactivity • Alpha • Beta – Beta minus – beta plus ( emission) – capture • Gamma – Isomeric transitions – – Internal • Cluster radioactivity • – Binary or ternary • Rare types: – radioactivity – b+ delayed – b- delayed emission – b+ delayed deuteron or triton emission – Beta delayed fission Fun with Isotopes supposedly follows a mathematically precise exponential function

• Supposedly unaffected by , pressure, chemical environment • First declared by , Chadwick and Ellis Generally true but… …well-known exceptions do exist …well-known exceptions do exist

• (e.g. 7Be, 109In, 110Sn) – If chemical environment make K-shell less accessible, decay rate might be altered …well-known exceptions do exist

• Electron Capture (e.g. 7Be, 109In, 110Sn) – If chemical environment make K-shell electrons less accessible, decay rate might be altered • Isomeric Transitions – 99mTc: observable half-life changes due to chemical environment

– T1/2 difference ~0.3% when in Tc2S7 vs NaTcO4 ( pertechnetate) in physiological saline Is it stable???

• Z > 83 ()???? – If so, the is unstable – Every (natural) element from 84 (Po) upwards is radioactive Is it stable???

• Z > 83 (bismuth)???? – If so, the isotope is unstable – Every (natural) element from 84 (Po) upwards is radioactive – Even Bi-209 might be unstable… – with an α-emission half-life of 1.9×1019 Is it stable???

• Recall: • Z = number of • N = number of • A = number of protons + neutrons (i.e. total number of ) • Are both Z and N even? – If so, the isotope is probably stable (e.g. C-12, O-16) • Are both Z and N odd? – If so, the isotope is probably unstable (e.g. F-18) • Oddness of both Z and N tends to lower the nuclear binding Odds of being stable

Protons Neutrons Number of Stable Stability

Odd Odd 4 least

Odd Even 50 less

Even Odd 57 more

Even Even 168 most Is it stable???

• Is there a “ number” of nucleons? – If so, the isotope is stable – Results in complete nuclear shells – High average per • Protons: 2, 8, 20, 28, 50, 82, 114 • Neutrons: 2, 8, 20, 28, 50, 82, 126, 184 Double the magic

• Nuclei with both N and Z each being one of the magic numbers are “double magic” • Only 10 of ~2500 nuclides • Unusually stable against decay (note: this does NOT mean they are absolutely stable!) • Some double magic isotopes include – -4 – -16 – -40 – -48 – nickel-78 – -208 Is it stable???

• What is the N:Z ratio? • Where is the isotope in relationship to the “zone of stability”? • In other words - Is it in the zone?

Regarding the zone • As Z increases, A must increase disproportionately for stability – Number of neutrons needed increases as the number of protons increases • Fe-56 is the most stable isotope (lowest per nucleon) – Below Fe-56 fusion can generate energy – Above Fe-56 fission can generate energy • No natural elements with Z > 83 (bismuth) are stable Regarding the zone • Stable nuclides contain about equal protons and neutrons • Stable heavy elements contain up to 1.6x more neutrons than protons • Nuclides above (to the left of) the band of stability are neutron-rich • Nuclides below (to the right of) the band are neutron deficient

Neutron-rich nuclides • To the left of the zone: Need more protons – Want to rid the excess n and produce more p • Below Z=83, neutron-rich radioisotopes decay via beta minus emission – (i.e. conversion of a neutron into a proton) • Above Z=83, neutron-rich nuclei also decay via alpha emission • Note: actually increases the n:p ratio 238 234 4 – e.g. U92  Th90 + He2 – 146n and 92p (n:p = 1.587) vs 144n and 90p (n:p = 1.6) – Daughters tend to be more n-rich than the parents Some more definitions

Examples

131 125 Isotopes Same Z, different A I53 I53

39 40 Same N, different A and/or Z Ar18 K19

228 228 Isobars Same A, different Z Ra88 Th90

235 231 Isodiaphers Excess mass (N-Z) is the same U92 Th90

Isomers Same Z, same A (different energy) 99mTc 99Tc • On this particular diagram style: • Isotopes on horizontal line • Isobars on NE line () • Alpha decay on vertical line Alpha decay

• Ejection of a Helium nucleus A A-4 4 • Xz  Yz-2 + He2 • Requires:

• Mx > My + MHe 210 206 4 – Poz  Pb + He2 – (209.9829u)  (205.9745u) + (4.0026u) • 209.9829u > 209.9771u Therefore a allowed • Cu-64 cannot alpha decay -210

• T1/2 = 138 days • 5.3 MeV • 166,500 TBq/kg (4500 Ci/g) • Extremely toxic: 1 mg can kill an average adult – ~250,000x more toxic than HCN by weight • Used to kill Russian dissident Alexander Litvinenko in 2006 -241 • A trans- • Ordinary household smoke detectors contain ~0.29 mg of americium dioxide • Am-241 alpha decays to Np-237

– T1/2 = 432.2 years • a collide with O and N molecules in the air • Generates in the chamber – Ions produce an between electrodes • Ions are neutralized upon contact with smoke – Decreasing the electric current – Activates the detector's alarm -238 • Half-life of 87.7 years • Powerful alpha emitter – Does not emit significant g • Radioisotope Thermoelectric Generators (RTGs) – Converts into via Seebeck effect – 1g Pu-238 generates approximately 0.5W – Voyager 1 and 2, Cassini–Huygens, New Horizons and the Mars Science Laboratory • 250 plutonium-powered cardiac pacemakers made: – 22 were still in service more than 25 years later – No battery-powered pacemaker could achieve that! -226

• T1/2 = 1600 years • Alpha decay to Rn-222 • 6th Member of the Uranium Series - ultimately ending in Pb-206 • 78 g rays from Ra-226 and decay products • Energy ranging from 0.184 MeV - 2.45 MeV (these are what were clinically useful) – Average 0.83 MeV • HVL 14 mm Pb • 0.5 mm Pt encapsulation for filtering Primordial decay series

• series (n) • series (4n+1) • Uranium series (4n+2) • series (4n+3) • Thorium series • 4n series

• " Thorium" by http://commons.wiki media.org/wiki/User: BatesIsBack - http://commons.wiki media.org/wiki/File:D ecay_Chain_of_Thoriu m.svg. Licensed under CC BY-SA 3.0 via Wikimedia Commons • Neptunium series • 4n+1 series • Extinct

• "Decay Chain(4n+1, Neptunium Series)" by BatesIsBack - http://commons.wikim edia.org/wiki/File:Deca y_chain(4n%2B1,Neptu nium_series).PNG. Licensed under CC BY 3.0 via Wikimedia Commons • Uranium series • 4n+2 series

• "Decay chain(4n+2, Uranium series)" by User:Tosaka - File:Decay chain(4n+2, Uranium series).PNG. Licensed under CC BY 3.0 via Wikimedia Commons - • Actinium series • 4n+3 series

• "Decay Chain of Actinium" by Edgar Bonet - Own . Licensed under CC BY-SA 3.0 via Wikimedia Commons - Radium Basics

• One gram of radium-226 undergoes 3.7 × 1010 disintegrations per second • Thirty-three – All radioactive • Half-lives (generally) short: – less than a few weeks – with the exceptions of radium-226 (1,600 years) and radium-228 (5.8 years)

40 Biological effects • Radium dermatitis: • Only 2 years after its discovery, A. Henri developed a skin ulcer after carrying an ampule in his pocket for six hours • Marie developed a skin ulcer after a few days following 10 hrs of direct contact with a tiny sample

41 “The Radium Craze” • 1903 - numerous commercially available products became available – Cosmos Bag for arthritis – Liquid Sunshine – Radiathor • The sad case of Eben Byers ended this era upon his death in 1932 – He consumed an estimated 1400 bottles of Radiathor – This Wall Street Journal line said it all: – "The Radium Water Worked Fine…

42 “The Radium Craze” • 1903 - numerous commercially available products became available – Cosmos Bag for arthritis – Liquid Sunshine – Radiathor • The sad case of Eben Byers ended this era upon his death in 1932 – He consumed an estimated 1400 bottles of Radiathor – This Wall Street Journal line said it all: – "The Radium Water Worked Fine until his jaw came off”

43 The Radium Girls

• U.S. Radium Corporation • Watch dial containing 70 mg/g of paint • Contained RaBr and ZnS (which glows upon alpha ) • Of 800 employees from 1917 to 1924, 48 developed radiation sickness (including mandibular necrosis) and 18 died (including cases of osteosarcoma)

The Great Radium Scandal. Roger Macklis. Scientific American 1993

44 So why is there possibly any interest in Radium today???

• Radium-223 is the isotope of interest presently • Part of the actinium series (4n + 3 series) • Radiologically well-suited for • 11.4-day half-life • 5.99 MeV alpha emission • First FDA-approved unsealed source alpha-emitting • Some compelling clinical data has emerged recently

45 Radium-223 Decay Chain

• Of the total 223Ra – 95.3% emitted as 11.43 d a particles α 219Rn – 3.6% emitted as 3.96 s b particles α

215 211 – 1.1% emitted as Po β− Po 1.78 ms 516 ms (0.27%) 211Bi g or x-rays α β− α 2.17 m • Easily measured on 211 207 Pb α (99.73%) β− Pb standard dose calibrators 36.1 m stable 207TI α 4.77 m

Henriksen et al. Res. 2002;62:3120-3125. 46 Nilsson et al Clin Cancer Res 2005

47 Radium-223

• Bone-seeking like the beta emitters Sr-89 and Sm-153 EDTMP • But Ra-223 is a high-LET alpha emitter • α-particles cause double-strand DNA – Limited penetration of α particles (~ 2-10 cell diameters) • In principle: – potentially more effective at killing tumor cells – less myelosuppressive due to range <100 mm of alpha particles

48 Spontaneous fission

• Although possible, not prevalent in • U-238 decays via spontaneous fission 2 million x slower than its already slow alpha decay (4.5 Ga vs 10 Pa) • For artificial radionuclides with Z>90, this does occur • Typically with emission of one or more neutrons (up to 10) An Isotopic Source of Neutrons: Cf-252

• Alpha decay (97%) and Fission (3%): – 252Cf  248Cm + 4a (96.9%) – 252Cf  fission + 1n (3.1%) • Average of 3.7 neutrons per fission • Neutron energy range of 0 to 13 MeV • Mean value of 2.1 MeV and most probable energy 0.7 MeV

• T1/2 = 2.64 years • Average energy 0.8 MeV and

• AKA Cluster Radioactivity or heavy particle radioactivity • Nucleus emits a small "cluster” of neutrons and protons – Larger than alpha particles – Smaller than a normal binary fission fragment • 223Ra → 209Pb + 14C • Ternary fission into three fragments can also produce products in this size range – Although 3rd fission product most often is a He nucleus Beta decay

• Parent and daughter are isobars • : “Beta minus” • : “Beta plus” • Electron capture • Can be considered “” • But inverse beta decay also refers to: Beta minus decay

• Converts a neutron into a proton (Z increases) • An electron is emitted from the nucleus • A SPECTRUM of • Neutron becomes a proton plus an electron plus an (electron) antineutrino • Recall that (n) exist in 3 flavors:

– ne, nm, nt • Equations must balance: – Mass (baryons) – Charge – /anti-matter – – Energy –

Welsh JS. Am J Clin Oncol 2007;30: 437–439) At a more granular level…

• A neutron (composed of 2 down and 1 up ) is converted into a proton (composed of 2 up quarks and 1 ) • In other words a down quark is converted into an • This “weak” interaction is mediated by a W- intermediate vector • Recall the 4 fundamental forces: – Gravity – – Strong nuclear – Weak nuclear

Positron emission

• A way to deal with excess protons • Competes with electron capture • Proton converted into a neutron plus a positron plus an (electron) • Recall that neutrinos exist in 3 flavors:

– ne, nm, nt • Same conservation rules: – Mass (baryons) – Charge – Matter/anti-matter – Lepton number – Energy – Momentum

-

Welsh JS. Am J Clin Oncol 2007;30: 437–439) At a more fundamental level

• A proton (uud) is converted into a neutron (ddu) • An up is converted into a down • Recall that up quarks carry +2/3 charge while down quarks carry -1/3 • Thus a +1 baryon (proton or uud) is converted into a charge zero baryon (neutron or udd) • Mediated by W+ boson

Electron capture

A 0 A • Xz + e-1  yZ-1 + ne 1 0 1 • p1 + e-1  n0 + ne • EC can only happen if: 2 • MA - MB > W/c 2 – (MA - MB)c > W • For 2 neighboring isobars on the , EC can occur only when difference between parent and daughter exceeds mass- energy equivalence of lowest electron binding energy of parent Electron capture

• Electron capture and positron emission both solve the problem of excess protons • Competing nuclear mechanisms • Positron emission wins out in low-Z elements – e.g. 11C, 15O, 18F • EC wins out in high-Z elements – e.g. 131Cs, 125I, 103Pd – Due to Coulombic attraction pulling electron cloud closer to nucleus – Some can do both

A variety of radiation can follow electron capture • Loss of an electron leaves a vacancy that is filled by cascading electrons from higher energy shells leading to characteristic x-rays • Instead of characteristic x-rays, Auger and Coster- Kronig electrons can be emitted • Capture of an electron leaves the nucleus in an • (Prompt) gamma photons or conversion electrons (via internal conversion) can be emitted from the nucleus Coster-Kronig and Auger electrons follow electron capture (compete with characteristic photons) Conversion electrons can also follow electron capture (compete with gamma photons) Conversion electrons can also follow electron capture (compete with gamma photons) Isomeric transition

• Excited nuclear state decays to ground level • No change in Z, N or A • Typically refers to metastable states transitioning to lower energy (as opposed to “prompt” ) • Results in emission of a • Example: 99mTc  99Tc + g (~140keV) – Note: reason for is difference in parent (+1/2) and daughter (+9/2) states • Competing with gamma photon production is internal conversion Internal conversion: “Conversion electrons” • Instead of a g emanating from the metastable isomer nucleus, an e- is ejected from the electron cloud • Can be thought of as an “internal ” – a virtual g interacts with and ejects an electron – More precisely, a 1s (or 2s or 3s) orbital e- wavefunction interacts with the nucleus and the excitation energy is directly transferred to the electron Internal conversion: “Conversion electrons” • Explains how half-life of Tc-99m can differ based on chemical environment… • If electrons are less available (because of chemical bonds pulling them away) conversion is less likely and the branching ratio and half life are affected! Internal conversion: “Conversion electrons” • More likely with high Z: – internal conversion ~Z3 – Conversion coefficient: (# of de-excitations via e) / (# of de- excitations via g) • Technically NOT beta decay since the electron originates from the orbital cloud rather than the nucleus – Also, conversion electrons are monoenergetic! Internal pair production • Also competes with gamma emission • An electron/positron pair emitted instead of a gamma photon or a conversion electron • Can happen if energy of the decay >2x the rest mass of the electron: 2 • Eg > 2mec (i.e. 0.511MeV x 2 = 1.02 MeV) Internal pair production • “…although 90Y has been traditionally considered as a pure β– emitter, the decay of this radionuclide has a minor branch to the 0+ first excited state of stable 90Zr at 1.76 MeV, which is followed by a β+/β– emission...” • …it was proposed to use this pair production in radiation in order to assess 90Y biodistribution by (PET)… • D'Arienzo M. Emission of β+ Particles Via Internal Pair Production in the 0+ – 0+ Transition of 90Zr: Historical Background and Current Applications in Imaging. . 2013; 1(1):2-12. • Selwyn, R.G.; Nickles, R.J.; Thomadsen, B.R.; DeWerd, L.A.; Micka, J.A. A new internal pair production branching ratio of 90Y: the development of a non-destructive assay for 90Y and 90Sr. Appl. Radiat. Isot. 2006, 65, 318–327. • 35 naturally occurring isotopes are capable of double beta decay – 2 neutrons in the nucleus are converted into 2 protons – 2 electrons (and two electron antineutrinos) are emitted • For double (or single) beta decay to occur, the final nucleus must have a larger binding energy than the original nucleus Double beta decay

• For some nuclei, (e.g. Ge-76), the nucleus one higher (As-76) has a smaller binding energy, preventing single beta decay • However, the nucleus with two greater protons (Se- 76) does have a higher binding energy • so double beta decay of Ge-76 is allowed • 35 naturally occurring isotopes are theoretically capable of double electron capture – 2 protons in the nucleus are converted into 2 neutrons by capturing two orbital electrons (and forming two electron neutrinos) • Z drops by 2 but A remains the same • Only experimentally confirmed for Ba-130 – (by detection of predicted daughter product Xe-130 in geological samples) 21 – T1/2…. 10 years! Postassium-40 decay • A primordial radionuclide 9 • T1/2 ~1.248 × 10 years • Major endogenous radionuclide • 0.012% (120 ppm) of all • 70 kg body contains ~160 total grams K and ~19mg 40K – 0.00012 x 160g = 0.0192 g of 40K • Decay continuously produces about 4,900 Bq • Quite unusual • THREE modes of decay – 88.8% beta minus – 12.2% electron capture – Tiny fraction (~0.001%) via positron emission

Beta emitters for bone metastases

• -89 • -32 • -153 • -166 • -188 • -117m Phosphorus-32

• Historical use dates back to 1940’s • Half-life = 14.3 days • Max beta energy = 1.71 MeV • Avg beta particle energy = 0.693 MeV • Significant marrow toxicity Strontium-89

• Half-life = 50.5 days • Ebmax= 1.463 MeV (100%) • Max range in tissue: 8 mm • Average soft-tissue range 2.4 mm • Decays to 89Y (a stable isotope) with emission of a negative beta and an electron antineutrino

Silberstein, et al. Society of Nuclear Medicine Procedure Guideline for Palliative Treatment of Painful Bone Metastases version 3.0 Jan, 2003 Strontium-89

• Biochemically acts as a calcium analogue 89 • Used as a chloride salt ( SrCl2) • Can be produced via: – 88Sr (n,g) 89Sr – 89Y (n,p) 89Sr . Possibly via nuclear transformations of the fission products in the decay chain 89Se→89Br→89Kr→89Rb→89Sr Samarium-153

• Beta and Gamma emitter • Beta: 640 keV (30%) 710 keV (50%) 810 keV (20%) • Gamma: 103 keV (29%) 70 keV (5.2%) 97 keV (1.3%) Samarium-153 • Produced in high yield and purity by neutron irradiation of isotopically enriched 152 samarium oxide ( Sm2O3) • 152Sm (n, g) 153Sm 152 1 153 • Sm2O3 + n ------> Sm + g • ( might be hindered by this approach?) • Physical half-life = 46.3 hours (1.93 days) • Complexed with ethylenediamine tetramethylene phosphonate (EDTMP or lexidronam) Holmium-166

 165Ho (n,g) 166Ho  Chelated to a phosphonate with skeletal uptake similar to Tc-99m-MDP  Primarily a beta emitter with a relatively high energy (Emax = 1.85 MeV)

 Eβavg = 0.67 MeV  May be useful for larger tumors  Half-life of 26.8 hours  Relatively high dose-rate  Minor gamma component (81 keV) suitable for imaging Re-188

Physical half life 17.00 h Maximum beta energy 2120.4 keV (71.1%) (abundance) 1965.4 keV (25.6%)

Gamma energy (abundance) 155.0 keV (15%)

Maximum penetration in 10 mm (average 3.1 mm) tissue Penetration of g-rays, β Particles and α Particles into Bone and Marrow

Figure from Brady D, Parker C, O’Sullivan J. Bone-Targeting Radiopharmaceuticals Including Radium-223. The Cancer Journal. 2013;19:71-78. Copyright © 2013 The Cancer Journal. Reprinted with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health.

93 Comments • Some gamma photons are low energy • EC agents like Pd-103 – Therapeutic radiation = gamma photons and characteristic x-rays – Dose distributions not much different from hi- energy betas • Some electrons are VERY short range – shorter than alpha particles • Auger and Coster-Kronig electrons • High-LET/RBE! Beta-Emitting Radionuclides Used in • Strontium-90 • Phosphorus-32 • Ytrium-90 Strontium-90

• T1/2 = 29 years (28.78y) • Beta decay to Y-90 and Y-90m with a maximum energy of about 0.5 MeV • Classic fission byproduct • Therapeutic radiation is primarily from 2.27 MeV betas from Y-90 • Pterygium eye applicators and coronary brachytherapy Ytrium-90

• T1/2 = 64.1 hours • Beta decay into Zr-90 with a maximum energy of 2.28 MeV • Range: 1.1 cm • Used in microspheres (resin and glass) for liver microsphere brachytherapy (“radioembolization”) Phosphorus-32

• T1/2 = 14 days (14.262d) • Beta decay to -32 with a maximum energy of 1.71 MeV 32 0 32 • P15 ----> e-1 + S16 • Average beta particle energy = 0.693 MeV • Intracavitary applications (colloidal) • Slightly more limited penetration than Sr-90 Electron Capture Radionuclides Used in Brachytherapy • -103 • -125 • Cesium-131 Pd-103 • Half life = 17.0 days • Avg 0.021 MeV (21 keV) x-rays 103 - 103 • Pd + e  Rh* + ne • Excited 103Rh emits characteristic X-rays, gamma photons, conversion electrons and Auger electrons • In the encapsulated “seed” form only the photons are of clinical relevance • range: 20-23 keV • Average ~21 keV • HVL 0.004 Pb I-125

• T1/2 = 60.1 days 125 - 125 • I + e  Te* + ne • Internal conversion 93% of time (yielding 27.0 keV and 31.0 keV x-rays; avg 28.5 keV) and produces a prompt gamma ray (35.5 keV) 7% of time • Average 0.028 MeV • HVL 0.025 mm Pb Cs-131

• T1/2 = 9.689 days 131 - 131 • Cs + e  Xe* + ne • Excited Xe-131 emits characteristic x-rays • 4-34 keV photons • Most prominent peaks in 29-34keV range • Average 30.4 keV Photon-Emitting Radionuclides Used in Brachytherapy and Teletherapy • Cesium-137 • -192 • -198 • Radium-226

• -60 Co-60

• Half life 5.263 yrs • Beta decay 60Co  60Ni + b- + g • Principal gamma rays produced: 1.17 MeV, 1.33 MeV • Average gamma energy = 1.25 MeV • Beta: 0.32 MeV (99%) and 1.48 MeV (1%) Emax Co-60 Radium-226

• T1/2 = 1600 years • Alpha decay to -222 and down to Pb-206 but the photons are what are used clinically • 78 g rays from Ra-226 and decay products • Energy ranging from 0.184 MeV - 2.45 MeV – Average 0.83 MeV • HVL 14 mm Pb • 0.5 mm Pt encapsulation for beta particle filtering Gold-198

• T1/2 = 2.7 days • Beta decays to Hg-198 • 0.412 MeV photons • Nearly monoenergetic • Also emits beta particles (maximum energy 0.96 MeV) • These electrons are absorbed by the 0.1mm thick wall of the seed) • HVL = 2.5 mm Pb Cesium-137

• T1/2 = 30.07 years • Beta decay to Ba-137m • 662 keV photons • Another classic fission product • HVL 5.5 mm Pb • Stainless steel encapsulation • Less shielding than Ra-226 • Typically needs replacement after 7 years Iridium-192

• T1/2 = 74 days (73.831d) • Beta decay to excited states of Pt-192 – AND • Electron capture to Os-192 • Complex energy spectrum • Average photon energy ~0.38 MeV • HVL 2.5 mm Pb Conclusions

• Isotopes are fun