2017
DOI: 10.1002/ange.201709532
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An Eighteen‐Membered Macrocyclic Ligand for Actinium‐225 Targeted Alpha Therapy

Abstract: The 18-membered macrocycle H 2 macropa was investigated for 225 Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225 Ac (26 kBq) in 5min at RT.[ 225 Ac(macropa)] + remained intact over 7t o 8dayswhen challenged with either excess La 3+ ions or human serum, and did not accumulate in any organ after 5hin healthy mice.Abifunctional analogue,macropa-NCS,was conjugated to trastuzumab as well as to the prostate-specific membrane an… Show more

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Cited by 31 publications
(56 citation statements)
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“…Notably,m acropa is also ah ighly effective chelator for 225 Ac 3 + , for use in targeted a particle therapy. [13] Having established effective chelators for 132/135 La, we next prepared conjugates of these ligands with ap rostate-specific membrane antigen-( PSMA)-targeting agent to demonstrate the biological utility of these isotopes. Our choice of PSMA-targeting ligand, the Glu-urea-Glu dipeptide, was motivated by the successful application of Glu-urea-Glua nd Glu-urea-Lys targeting vectors in relatedr adiometal-based diagnostic and therapeutic constructs employing 99m Tc , 68 Ga, 177 Lu, 111 In, 225 Ac, 44 Sc, and other radionuclides.…”
Section: /135mentioning
confidence: 99%
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“…Notably,m acropa is also ah ighly effective chelator for 225 Ac 3 + , for use in targeted a particle therapy. [13] Having established effective chelators for 132/135 La, we next prepared conjugates of these ligands with ap rostate-specific membrane antigen-( PSMA)-targeting agent to demonstrate the biological utility of these isotopes. Our choice of PSMA-targeting ligand, the Glu-urea-Glu dipeptide, was motivated by the successful application of Glu-urea-Glua nd Glu-urea-Lys targeting vectors in relatedr adiometal-based diagnostic and therapeutic constructs employing 99m Tc , 68 Ga, 177 Lu, 111 In, 225 Ac, 44 Sc, and other radionuclides.…”
Section: /135mentioning
confidence: 99%
“…Our choice of PSMA-targeting ligand, the Glu-urea-Glu dipeptide, was motivated by the successful application of Glu-urea-Glua nd Glu-urea-Lys targeting vectors in relatedr adiometal-based diagnostic and therapeutic constructs employing 99m Tc , 68 Ga, 177 Lu, 111 In, 225 Ac, 44 Sc, and other radionuclides. [13][14] Our synthesis (see SI for more details) commenced with the preparation of DUPA ( Figure 1), an aliphatic,a mino-pentylamine linker version of the Glu-urea-Glu dipeptide that mimics the structural components of the clinically validated 99m Tc -basedp rostate cancer-imaging agent MIP-1427. [14d] The reactive primary amine of this compound was then conjugated to macropaa nd DO3Apic.…”
Section: /135mentioning
confidence: 99%
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“…A pioneering, successful application triggered a dramatically increased interest and has revived research on Ac IIIand Bi III -chelators as well as the corresponding labeling chemistry. 34,35 It is to be expected that coming years will see a strong surge in production capacities for 225 Ac and the corresponding 225 Ac/ 213 Bi radionuclide generators. 36 This, in turn, will foster development of novel alpha-emitter labeled therapeutics and very soon will greatly increase these nuclides' popularity, as reflected by growing numbers of publication and cites.…”
Section: The Rise Of Theranosticsmentioning
confidence: 99%
“…Macropa incorporates ether and amino donors within the macrocycle as well as bidentate picolinate donor arms to match the size and hardness of Ac 3+ , showing promise for targeted applications. 127 Due to the limited access to 225 Ac, only a handful of human studies have been carried out, but both preclinical and clinical work on therapeutic applications of this isotope have provided promising treatment outcomes. Multiple clinical trials involving 225 Ac lintuzumab, an anti-CD33 mAb (HuM195) for the treatment of acute myeloid leukemia, are ongoing, taking advantage of the multidaughter decay scheme of 225 Ac as an advantage over the 213 Bi-analogue; preliminary data show a 3 orders of magnitude greater potency of 225 Ac-HuM195 when compared with 213 Bi-HuM195 (www.clinicaltrials.gov).…”
mentioning
confidence: 99%