View source for Engineering:Targeted alpha-particle therapy

'''Targeted alpha-particle therapy''' (or '''TAT''') is an in-development method of targeted [[Physics:Radionuclide|radionuclide]] therapy of various [[Medicine:Cancer|cancer]]s. It employs [[Physics:Radioactive|radioactive]] substances which undergo [[Physics:Alpha decay|alpha decay]] to treat diseased tissue at close proximity.<ref>{{Cite book |title=Advancing nuclear medicine through innovation |last1=Committee on State of the Science of Nuclear Medicine |last2=National Research Council |last3=Division on Earth and Life Studies |last4=Institute of Medicine |last5=Nuclear and Radiation Studies Board |last6= Board on Health Sciences Policy |date=2007 |publisher=National Academies Press |isbn=978-0-309-11067-9 |location=Washington, D.C. |publication-date=2007 |chapter=Targeted Radionuclide Therapy |doi=10.17226/11985 |pmid=20669430 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK11464/}}</ref> It has the potential to provide highly targeted treatment, especially to microscopic tumour [[Biology:Cell|cells]]. Targets include [[Medicine:Leukemia|leukemia]]s, [[Medicine:Lymphoma|lymphoma]]s, gliomas, [[Medicine:Melanoma|melanoma]], and peritoneal carcinomatosis.<ref>{{cite journal|last1=Mulford|first1=DA|last2=Scheinberg|first2=DA|last3=Jurcic|first3=JG|title=The promise of targeted {alpha}-particle therapy.|journal=Journal of Nuclear Medicine |date=January 2005|volume=46|issue=Suppl 1 |pages=199S–204S|pmid=15653670|url=http://jnm.snmjournals.org/content/46/1_suppl/199S.long}}</ref> As in diagnostic [[Medicine:Nuclear medicine|nuclear medicine]], appropriate radionuclides can be [[Chemistry:Chemical bond|chemically bound]] to a targeting [[Physics:Biomolecule|biomolecule]] which carries the combined [[Medicine:Radiopharmaceutical|radiopharmaceutical]] to a specific treatment point.<ref name="Dekempeneer16">{{cite journal|last1=Dekempeneer|first1=Yana|last2=Keyaerts|first2=Marleen|last3=Krasniqi|first3=Ahmet|last4=Puttemans|first4=Janik|last5=Muyldermans|first5=Serge|last6=Lahoutte|first6=Tony|last7=D’huyvetter|first7=Matthias|last8=Devoogdt|first8=Nick|title=Targeted alpha therapy using short-lived alpha-particles and the promise of nanobodies as targeting vehicle|journal=Expert Opinion on Biological Therapy|date=19 May 2016|volume=16|issue=8|pages=1035–1047|doi=10.1080/14712598.2016.1185412|pmid=27145158|pmc=4940885}}</ref>
It has been said that "α-emitters are indispensable with regard to optimisation of strategies for tumour therapy".<ref name="Seidl11">{{cite book|last1=Seidl|first1=Christof|last2=Senekowitsch-Schmidtke|first2=Reingard|editor1-last=Baum|editor1-first=Richard P.|title=Therapeutic nuclear medicine|date=2011|publisher=Springer|location=Berlin|isbn=978-3-540-36718-5|pages=557–567|chapter=Targeted Alpha Particle Therapy of Peritoneal Carcinomas|doi=10.1007/174_2012_678}}</ref>

==Advantages of alpha emitters==
[[File:SEM - range of α and β− particles.jpg|thumb|right|Comparison of range of α (red) and β− (white) particles]]
The primary advantage of [[Physics:Alpha particle|alpha particle]] (α) emitters over other types of radioactive sources is their very high [[Physics:Linear energy transfer|linear energy transfer]] (LET) and [[Biology:Relative biological effectiveness|relative biological effectiveness]] (RBE).<ref>{{cite book|last1=Kane|first1=Suzanne Amador|title=Introduction to physics in modern medicine|date=2003|publisher=Taylor & Francis|location=London|isbn=9780415299633|page=243|edition=Repr.}}</ref> [[Physics:Beta particle|Beta particle]] (β) emitters such as [[Physics:Yttrium-90|yttrium-90]] can travel considerable distances beyond the immediate tissue before depositing their energy, while alpha particles deposit their energy in 70–100 μm long tracks.<ref>{{cite journal|last1=Elgqvist|first1=Jörgen|last2=Frost|first2=Sofia|last3=Pouget|first3=Jean-Pierre|last4=Albertsson|first4=Per|title=The Potential and Hurdles of Targeted Alpha Therapy – Clinical Trials and Beyond|journal=Frontiers in Oncology|date=2014|volume=3|pages=324|doi=10.3389/fonc.2013.00324|pmid=24459634|pmc=3890691|doi-access=free}}</ref>

Alpha particles are more likely than other types of radiation to cause [[Biology:DNA repair#Double-strand breaks|double-strand breaks]] to DNA molecules, which is one of several effective causes of [[Biology:Cell death|cell death]].<ref>{{cite book|last1=Baum|first1=Richard P|title=Therapeutic Nuclear Medicine|date=2014|publisher=Springer|location=Heidelberg|isbn=9783540367192|page=98}}</ref><ref>{{cite journal|last1=Hodgkins|first1=Paul S.|last2=O'Neill|first2=Peter|last3=Stevens|first3=David|last4=Fairman|first4=Micaela P.|title=The Severity of Alpha-Particle-Induced DNA Damage Is Revealed by Exposure to Cell-Free Extracts|journal=Radiation Research|date=December 1996|volume=146|issue=6|pages=660–7|doi=10.2307/3579382|pmid=8955716|jstor=3579382|bibcode=1996RadR..146..660H}}</ref>

==Production==
Some α emitting isotopes such as [[Physics:Actinium-225|<sup>225</sup>Ac]] and [[Physics:Bismuth-213|<sup>213</sup>Bi]] are only available in limited quantities from [[Physics:Thorium-229|<sup>229</sup>Th]] decay, although [[Physics:Cyclotron|cyclotron]] production is feasible.<ref name="Seidl14">{{cite journal|last1=Seidl|first1=Christof|title=Radioimmunotherapy with α-particle-emitting radionuclides|journal=Immunotherapy|date=April 2014|volume=6|issue=4|pages=431–458|doi=10.2217/imt.14.16|pmid=24815783}}</ref><ref>{{cite journal|last1=Apostolidis|first1=C.|last2=Molinet|first2=R.|last3=McGinley|first3=J.|last4=Abbas|first4=K.|last5=Möllenbeck|first5=J.|last6=Morgenstern|first6=A.|title=Cyclotron production of Ac-225 for targeted alpha therapy|journal=Applied Radiation and Isotopes|date=March 2005|volume=62|issue=3|pages=383–387|doi=10.1016/j.apradiso.2004.06.013|pmid=15607913}}</ref><ref>{{cite journal|last1=Miederer|first1=Matthias|last2=Scheinberg|first2=David A.|last3=McDevitt|first3=Michael R.|title=Realizing the potential of the Actinium-225 radionuclide generator in targeted alpha particle therapy applications|journal=Advanced Drug Delivery Reviews|date=September 2008|volume=60|issue=12|pages=1371–1382|doi=10.1016/j.addr.2008.04.009|pmid=18514364|pmc=3630456}}</ref> Among alpha-emitting radiometals according to availability, chelation chemistry, and half-life, [[Chemistry:Lead|<sup>212</sup>Pb]] is also a promising candidate for targeted alpha-therapy.<ref>{{Cite journal |last1=Kokov |first1=K.V. |last2=Egorova |first2=B.V. |last3=German |first3=M.N. |last4=Klabukov |first4=I.D. |last5=Krasheninnikov |first5=M.E. |last6=Larkin-Kondrov |first6=A.A. |last7=Makoveeva |first7=K.A. |last8=Ovchinnikov |first8=M.V. |last9=Sidorova |first9=M.V. |last10=Chuvilin |first10=D.Y. |date=2022 |title=212Pb: Production Approaches and Targeted Therapy Applications |journal=Pharmaceutics |volume=14 |issue=1 |pages=189 |doi=10.3390/pharmaceutics14010189 |issn=1999-4923 |pmc=8777968 |pmid=35057083|doi-access=free }}</ref><ref>{{Cite journal |last1=Yang |first1=Hua |last2=Wilson |first2=Justin J. |last3=Orvig |first3=Chris |last4=Li |first4=Yawen |last5=Wilbur |first5=D. Scott |last6=Ramogida |first6=Caterina F. |last7=Radchenko |first7=Valery |last8=Schaffer |first8=Paul |date=2022 |title=Harnessing α-Emitting Radionuclides for Therapy: Radiolabeling Method Review |journal=Journal of Nuclear Medicine |volume=63 |issue=1 |pages=5–13 |doi=10.2967/jnumed.121.262687 |issn=1535-5667 |pmc=8717181 |pmid=34503958}}</ref>

The ARRONAX cyclotron can produce [[Physics:Astatine-211|<sup>211</sup>At]] by irradiation of [[Physics:Bismuth-209|<sup>209</sup>Bi]].<ref>{{cite journal|last1=Haddad|first1=Ferid|last2=Barbet|first2=Jacques|last3=Chatal|first3=Jean-Francois|title=The ARRONAX Project|journal= Current Radiopharmaceuticals|date=1 July 2011|volume=4|issue=3|pages=186–196|doi=10.2174/1874471011104030186|pmid=22201708}}</ref><ref name="Seidl14" />

==Applications==
Though many α-emitters exist, useful isotopes would have a sufficient energy to cause damage to cancer cells, and a [[Physics:Half-life|half-life]] that is long enough to provide a therapeutic dose without remaining long enough to damage healthy tissue.

===Immunotherapy===
Several radionuclides have been studied for use in [[Medicine:Immunotherapy|immunotherapy]]. Though β-emitters are more popular, in part due to their availability, trials have taken place involving <sup>225</sup>Ac, <sup>211</sup>At, <sup>212</sup>Pb and <sup>213</sup>Bi.<ref name="Seidl14" />

===Peritoneal carcinomas===
Treatment of peritoneal carcinomas has promising early results limited by availability of α-emitters compared to β-emitters.<ref name="Seidl11" />

===Bone metastases===
[[Chemistry:Radium-223|<sup>223</sup>Ra]] was the first α-emitter approved by the FDA in the United States for treatment of bone metastases from [[Medicine:Prostate cancer|prostate cancer]], and is a recommended treatment in the UK by NICE.<ref name="Dekempeneer16" /><ref>{{cite web|title=Radium-223 dichloride for treating hormone-relapsed prostate cancer with bone metastases|url=https://www.nice.org.uk/guidance/ta412/chapter/1-recommendations|website=National Institute for Health and Care Excellence|date=28 September 2016 |accessdate=19 December 2016}}</ref> In a phase III trial comparing [[Chemistry:Radium-223|<sup>223</sup>Ra]] to a [[Medicine:Placebo|placebo]], survival was significantly improved.<ref>{{cite journal|last1=Parker|first1=C.|last2=Nilsson|first2=S.|last3=Heinrich|first3=D.|last4=Helle|first4=S.I.|last5=O'Sullivan|first5=J.M.|last6=Fosså|first6=S.D.|last7=Chodacki|first7=A.|last8=Wiechno|first8=P.|last9=Logue|first9=J.|last10=Seke|first10=M.|last11=Widmark|first11=A.|last12=Johannessen|first12=D.C.|last13=Hoskin|first13=P.|last14=Bottomley|first14=D.|last15=James|first15=N.D.|last16=Solberg|first16=A.|last17=Syndikus|first17=I.|last18=Kliment|first18=J.|last19=Wedel|first19=S.|last20=Boehmer|first20=S.|last21=Dall'Oglio|first21=M.|last22=Franzén|first22=L.|last23=Coleman|first23=R.|last24=Vogelzang|first24=N.J.|last25=O'Bryan-Tear|first25=C.G.|last26=Staudacher|first26=K.|last27=Garcia-Vargas|first27=J.|last28=Shan|first28=M.|last29=Bruland|first29=Ø.S.|last30=Sartor|first30=O.|title=Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer|journal=New England Journal of Medicine|date=18 July 2013|volume=369|issue=3|pages=213–223|doi=10.1056/NEJMoa1213755|pmid=23863050|doi-access=free}}</ref>

===Leukaemia===
Early trials of <sup>225</sup>Ac and <sup>213</sup>Bi have shown evidence of anti-tumour activity in Leukaemia patients.<ref>{{cite journal|last1=Jurcic|first1=Joseph G.|last2=Rosenblat|first2=Todd L.|title=Targeted Alpha-Particle Immunotherapy for Acute Myeloid Leukemia|journal=American Society of Clinical Oncology Educational Book|date=2014|volume=34|issue=34|pages=e126–e131|doi=10.14694/EdBook_AM.2014.34.e126|pmid=24857092|doi-access=free}}</ref>

===Melanomas===
Phase I trials on [[Medicine:Melanoma|melanoma]]s have shown <sup>213</sup>Bi is effective in causing tumour [[Medicine:Regression|regression]].<ref>{{cite journal|last1=Allen|first1=Barry J|last2=Raja|first2=Chand|last3=Rizvi|first3=Syed|last4=Li|first4=Yong|last5=Tsui|first5=Wendy|last6=Zhang|first6=David|last7=Song|first7=Emma|last8=Qu|first8=Chang Fa|last9=Kearsley|first9=John|last10=Graham|first10=Peter|last11=Thompson|first11=John|title=Targeted alpha therapy for cancer|journal=Physics in Medicine and Biology|date=21 August 2004|volume=49|issue=16|pages=3703–3712|doi=10.1088/0031-9155/49/16/016|pmid=15446799|bibcode=2004PMB....49.3703A|s2cid=250862050 }}</ref><ref>{{cite journal|last1=Kim|first1=Young-Seung|last2=Brechbiel|first2=Martin W.|title=An overview of targeted alpha therapy|journal=Tumor Biology|date=6 December 2011|volume=33|issue=3|pages=573–590|doi=10.1007/s13277-011-0286-y|pmid=22143940|url=https://zenodo.org/record/1232972|pmc=7450491}}</ref>

===Solid tumours===
The short [[Physics:Radiation length|path length]] of alpha particles in tissue, which makes them well suited to treatment of the above types of disease, is a negative when it comes to treatment of larger bodies of solid tumour by intravenous injection.<ref>{{cite journal|last1=Larson|first1=Steven M.|last2=Carrasquillo|first2=Jorge A.|last3=Cheung|first3=Nai-Kong V.|last4=Press|first4=Oliver W.|title=Radioimmunotherapy of human tumours|journal=Nature Reviews Cancer|date=22 May 2015|volume=15|issue=6|pages=347–360|doi=10.1038/nrc3925|pmid=25998714|pmc=4798425}}</ref><ref>{{cite journal|last1=Sofou|first1=S|title=Radionuclide carriers for targeting of cancer.|journal=International Journal of Nanomedicine|date=2008|volume=3|issue=2|pages=181–99|pmc=2527672|pmid=18686778|doi=10.2147/ijn.s2736|doi-access=free}}</ref> Potential methods to solve this problem of delivery exist, such as direct intratumoral injection<ref>{{cite journal|last1=Arazi|first1=L|last2=Cooks|first2=T|last3=Schmidt|first3=M|last4=Keisari|first4=Y|last5=Kelson|first5=I|title=Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters|journal=Physics in Medicine and Biology|date=21 August 2007|volume=52|issue=16|pages=5025–5042|doi=10.1088/0031-9155/52/16/021|pmid=17671351|bibcode=2007PMB....52.5025A|s2cid=1585204}}</ref> and [[Biology:Angiogenesis inhibitor|anti-angiogenic drugs]].<ref>{{cite journal|last1=Huang|first1=Chen-Yu|last2=Pourgholami|first2=Mohammad H.|last3=Allen|first3=Barry J.|title=Optimizing radioimmunoconjugate delivery in the treatment of solid tumor|journal=Cancer Treatment Reviews|date=November 2012|volume=38|issue=7|pages=854–860|doi=10.1016/j.ctrv.2011.12.005|pmid=22226242}}</ref><ref name="Dekempeneer16"/> Limited treatment experience of low grade malignant gliomas has shown possible efficacy.<ref>{{cite journal|last1=Cordier|first1=Dominik|last2=Krolicki|first2=Leszek|last3=Morgenstern|first3=Alfred|last4=Merlo|first4=Adrian|title=Targeted Radiolabeled Compounds in Glioma Therapy|journal=Seminars in Nuclear Medicine|date=May 2016|volume=46|issue=3|pages=243–249|doi=10.1053/j.semnuclmed.2016.01.009|pmid=27067505}}</ref>

==See also==
*[[Medicine:Unsealed source radiotherapy|Unsealed source radiotherapy]]
*[[Medicine:Selective internal radiation therapy|Selective internal radiation therapy]]

==References==
{{reflist|30em}}

{{Nuclear technology}}

[[Category:Nuclear technology]]
[[Category:Nuclear medicine]]
[[Category:Medical physics]]
[[Category:Cancer treatments]]

{{Sourceattribution|Targeted alpha-particle therapy}}