An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy

Nikki A. Thiele; Victoria Brown; James M. Kelly; Alejandro Amor-Coarasa; Una Jermilova; Samantha N. MacMillan; Anastasia Nikolopoulou; Shashikanth Ponnala; Caterina F. Ramogida; Andrew K.H. Robertson; Cristina Rodríguez-Rodríguez; Paul Schaffer; Clarence Williams; John W. Babich; Valery Radchenko; Justin J. Wilson

doi:10.1002/anie.201709532

An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy

Nikki A. Thiele, Victoria Brown, James M. Kelly, Alejandro Amor-Coarasa, Una Jermilova, Samantha N. MacMillan, Anastasia Nikolopoulou, Shashikanth Ponnala, Caterina F. Ramogida, Andrew K.H. Robertson, Cristina Rodríguez-Rodríguez, Paul Schaffer, Clarence Williams, John W. Babich, Valery Radchenko, Justin J. Wilson

Research output: Contribution to journal › Article › peer-review

179 Scopus citations

Abstract

The 18-membered macrocycle H₂macropa was investigated for ²²⁵Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all ²²⁵Ac (26 kBq) in 5 min at RT. [²²⁵Ac(macropa)]⁺ remained intact over 7 to 8 days when challenged with either excess La³⁺ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled ²²⁵Ac in just minutes at RT, and macropa-Tmab retained >99 % of its ²²⁵Ac in human serum after 7 days. In LNCaP xenograft mice, ²²⁵Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free ²²⁵Ac over 96 h. These findings establish macropa to be a highly promising ligand for ²²⁵Ac chelation that will facilitate the clinical development of ²²⁵Ac TAT for the treatment of soft-tissue metastases.

Original language	English
Pages (from-to)	14712-14717
Number of pages	6
Journal	Angewandte Chemie - International Edition
Volume	56
Issue number	46
DOIs	https://doi.org/10.1002/anie.201709532
State	Published - Nov 13 2017
Externally published	Yes

Funding

This work was supported by Cornell University and by a Pilot Award from the Weill Cornell Medical College Clinical and Translational Science Center, funded by NIH/NCATS UL1TR00457. This research made use of the NMR Facility at Cornell University, which is supported in part by the NSF under award number CHE-1531632. TRIUMF receives funding via a contribution agreement with the National Research Council of Canada. We thank TRIUMF≫s ISAC facility for ion beam delivery and Drs. Peter Kunz and Jens Lassen for help with collecting 225Ac and 225Ra samples. We also thank Dr. Eszter Boros at Stony Brook University for providing us with trastuzumab, and Dr. J. David Warren of the Milstein Core Chemistry Facility at Weill Cornell Medicine for the use of equipment for analysis and purification.

Funders	Funder number
NIH/NCATS	UL1TR00457
National Science Foundation	CHE-1531632
National Center for Advancing Translational Sciences	UL1TR000457
Cornell University
Weill Cornell Medical College
National Research Council Canada

Keywords

actinium
cancer
chelates
macrocycles
radiopharmaceuticals

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/anie.201709532

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Thiele, N. A., Brown, V., Kelly, J. M., Amor-Coarasa, A., Jermilova, U., MacMillan, S. N., Nikolopoulou, A., Ponnala, S., Ramogida, C. F., Robertson, A. K. H., Rodríguez-Rodríguez, C., Schaffer, P., Williams, C., Babich, J. W., Radchenko, V., & Wilson, J. J. (2017). An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy. Angewandte Chemie - International Edition, 56(46), 14712-14717. https://doi.org/10.1002/anie.201709532

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title = "An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy",

abstract = "The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.",

keywords = "actinium, cancer, chelates, macrocycles, radiopharmaceuticals",

author = "Thiele, {Nikki A.} and Victoria Brown and Kelly, {James M.} and Alejandro Amor-Coarasa and Una Jermilova and MacMillan, {Samantha N.} and Anastasia Nikolopoulou and Shashikanth Ponnala and Ramogida, {Caterina F.} and Robertson, {Andrew K.H.} and Cristina Rodr{\'i}guez-Rodr{\'i}guez and Paul Schaffer and Clarence Williams and Babich, {John W.} and Valery Radchenko and Wilson, {Justin J.}",

note = "Publisher Copyright: {\textcopyright} 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.",

year = "2017",

month = nov,

day = "13",

doi = "10.1002/anie.201709532",

language = "English",

volume = "56",

pages = "14712--14717",

journal = "Angewandte Chemie - International Edition",

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Thiele, NA, Brown, V, Kelly, JM, Amor-Coarasa, A, Jermilova, U, MacMillan, SN, Nikolopoulou, A, Ponnala, S, Ramogida, CF, Robertson, AKH, Rodríguez-Rodríguez, C, Schaffer, P, Williams, C, Babich, JW, Radchenko, V & Wilson, JJ 2017, 'An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy', Angewandte Chemie - International Edition, vol. 56, no. 46, pp. 14712-14717. https://doi.org/10.1002/anie.201709532

TY - JOUR

T1 - An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy

AU - Thiele, Nikki A.

AU - Brown, Victoria

AU - Kelly, James M.

AU - Amor-Coarasa, Alejandro

AU - Jermilova, Una

AU - MacMillan, Samantha N.

AU - Nikolopoulou, Anastasia

AU - Ponnala, Shashikanth

AU - Ramogida, Caterina F.

AU - Robertson, Andrew K.H.

AU - Rodríguez-Rodríguez, Cristina

AU - Schaffer, Paul

AU - Williams, Clarence

AU - Babich, John W.

AU - Radchenko, Valery

AU - Wilson, Justin J.

PY - 2017/11/13

Y1 - 2017/11/13

N2 - The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.

AB - The 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.

KW - actinium

KW - cancer

KW - chelates

KW - macrocycles

KW - radiopharmaceuticals

UR - http://www.scopus.com/inward/record.url?scp=85031428200&partnerID=8YFLogxK

U2 - 10.1002/anie.201709532

DO - 10.1002/anie.201709532

M3 - Article

C2 - 28963750

AN - SCOPUS:85031428200

SN - 1433-7851

VL - 56

SP - 14712

EP - 14717

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 46

ER -

An Eighteen-Membered Macrocyclic Ligand for Actinium-225 Targeted Alpha Therapy

Abstract

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Keywords

UN SDGs

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