225Ac-MACROPATATE: A Novel a-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

A. Paden King; Nicholas T. Gutsche; Natarajan Raju; Stanley Fayn; Kwamena E. Baidoo; Meghan M. Bell; Colleen S. Olkowski; Rolf E. Swenson; Frank I. Lin; Samira M. Sadowski; Stephen S. Adler; Nikki A. Thiele; Justin J. Wilson; Peter L. Choyke; Freddy E. Escorcia

doi:10.2967/jnumed.122.264707

²²⁵Ac-MACROPATATE: A Novel a-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

A. Paden King, Nicholas T. Gutsche, Natarajan Raju, Stanley Fayn, Kwamena E. Baidoo, Meghan M. Bell, Colleen S. Olkowski, Rolf E. Swenson, Frank I. Lin, Samira M. Sadowski, Stephen S. Adler, Nikki A. Thiele, Justin J. Wilson, Peter L. Choyke, Freddy E. Escorcia

Chemical Separations Group

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

20 Scopus citations

Abstract

Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE (DOTA-octreotate), a b-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted a-particle therapy has been shown to kill tumors that are resistant to targeted b-particle therapy, suggesting that targeted a-particle therapy may offer a promising treatment option for patients with ¹⁷⁷Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant a-particle–emitting radionuclide ²²⁵Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating ²²⁵Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. ²²⁵Ac-MACROPATATE demonstrated superior serum stability at 37^°C over time compared with ²²⁵Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of ²²⁵Ac-MACROPATATE than of ²²⁵Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that ²²⁵Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of ²²⁵Ac-MACROPA-TATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with ²²⁵Ac-DOTATATE. Conclusion: ²²⁵Ac-MACROPATATE and ²²⁵Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of ²²⁵Ac-MACROPATATE, ²²⁵Ac-DOTATATE was deemed the superior agent for targeted a-particle peptide receptor radionuclide therapy.

Original language	English
Pages (from-to)	549-554
Number of pages	6
Journal	Journal of Nuclear Medicine
Volume	64
Issue number	4
DOIs	https://doi.org/10.2967/jnumed.122.264707
State	Published - Apr 1 2023

Funding

This work was supported in part by the National Institutes of Biomedical Imaging and Bioengineering of the National Institutes of Health (awards R21EB027282 and R01EB029259), as well as by the National Cancer Institute from Intramural Research Program funds ZIA BC 011800 and ZIA BC 010891. This project was funded in whole or in part by the National Cancer Institute, National Institutes of Health, under contract 75N91019D00024. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Justin Wilson and Nikki Thiele are authors of a patent for the use of MACROPA as a chelator for 225Ac chelation. No other potential conflict of interest relevant to this article was reported.

Funders	Funder number
National Institutes of Health	R01EB029259, R21EB027282
National Cancer Institute	ZIA BC 010891, 75N91019D00024, ZIA BC 011800
National Institute of Biomedical Imaging and Bioengineering

Keywords

actinium
neuroendocrine tumors
octreotate
oncology
somatostatin
targeted a-therapy

UN SDGs

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

Access to Document

10.2967/jnumed.122.264707

Cite this

King, A. P., Gutsche, N. T., Raju, N., Fayn, S., Baidoo, K. E., Bell, M. M., Olkowski, C. S., Swenson, R. E., Lin, F. I., Sadowski, S. M., Adler, S. S., Thiele, N. A., Wilson, J. J., Choyke, P. L., & Escorcia, F. E. (2023). ²²⁵Ac-MACROPATATE: A Novel a-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors. Journal of Nuclear Medicine, 64(4), 549-554. https://doi.org/10.2967/jnumed.122.264707

@article{d81273803fc5490e8cd4ac8f62938378,

title = "225Ac-MACROPATATE: A Novel a-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors",

abstract = "Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with 177Lu-DOTATATE (DOTA-octreotate), a b-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted a-particle therapy has been shown to kill tumors that are resistant to targeted b-particle therapy, suggesting that targeted a-particle therapy may offer a promising treatment option for patients with 177Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant a-particle–emitting radionuclide 225Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating 225Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. 225Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with 225Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of 225Ac-MACROPATATE than of 225Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that 225Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of 225Ac-MACROPA-TATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 225Ac-DOTATATE. Conclusion: 225Ac-MACROPATATE and 225Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of 225Ac-MACROPATATE, 225Ac-DOTATATE was deemed the superior agent for targeted a-particle peptide receptor radionuclide therapy.",

keywords = "actinium, neuroendocrine tumors, octreotate, oncology, somatostatin, targeted a-therapy",

author = "King, {A. Paden} and Gutsche, {Nicholas T.} and Natarajan Raju and Stanley Fayn and Baidoo, {Kwamena E.} and Bell, {Meghan M.} and Olkowski, {Colleen S.} and Swenson, {Rolf E.} and Lin, {Frank I.} and Sadowski, {Samira M.} and Adler, {Stephen S.} and Thiele, {Nikki A.} and Wilson, {Justin J.} and Choyke, {Peter L.} and Escorcia, {Freddy E.}",

note = "Publisher Copyright: COPYRIGHT {\textcopyright} 2023 by the Society of Nuclear Medicine and Molecular Imaging.",

year = "2023",

month = apr,

day = "1",

doi = "10.2967/jnumed.122.264707",

language = "English",

volume = "64",

pages = "549--554",

journal = "Journal of Nuclear Medicine",

issn = "0161-5505",

publisher = "Society of Nuclear Medicine and Molecular Imaging",

number = "4",

}

King, AP, Gutsche, NT, Raju, N, Fayn, S, Baidoo, KE, Bell, MM, Olkowski, CS, Swenson, RE, Lin, FI, Sadowski, SM, Adler, SS, Thiele, NA, Wilson, JJ, Choyke, PL & Escorcia, FE 2023, '²²⁵Ac-MACROPATATE: A Novel a-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors', Journal of Nuclear Medicine, vol. 64, no. 4, pp. 549-554. https://doi.org/10.2967/jnumed.122.264707

TY - JOUR

T1 - 225Ac-MACROPATATE

T2 - A Novel a-Particle Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumors

AU - King, A. Paden

AU - Gutsche, Nicholas T.

AU - Raju, Natarajan

AU - Fayn, Stanley

AU - Baidoo, Kwamena E.

AU - Bell, Meghan M.

AU - Olkowski, Colleen S.

AU - Swenson, Rolf E.

AU - Lin, Frank I.

AU - Sadowski, Samira M.

AU - Adler, Stephen S.

AU - Thiele, Nikki A.

AU - Wilson, Justin J.

AU - Choyke, Peter L.

AU - Escorcia, Freddy E.

PY - 2023/4/1

Y1 - 2023/4/1

N2 - Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with 177Lu-DOTATATE (DOTA-octreotate), a b-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted a-particle therapy has been shown to kill tumors that are resistant to targeted b-particle therapy, suggesting that targeted a-particle therapy may offer a promising treatment option for patients with 177Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant a-particle–emitting radionuclide 225Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating 225Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. 225Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with 225Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of 225Ac-MACROPATATE than of 225Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that 225Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of 225Ac-MACROPA-TATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 225Ac-DOTATATE. Conclusion: 225Ac-MACROPATATE and 225Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of 225Ac-MACROPATATE, 225Ac-DOTATATE was deemed the superior agent for targeted a-particle peptide receptor radionuclide therapy.

AB - Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with 177Lu-DOTATATE (DOTA-octreotate), a b-particle–emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted a-particle therapy has been shown to kill tumors that are resistant to targeted b-particle therapy, suggesting that targeted a-particle therapy may offer a promising treatment option for patients with 177Lu-DOTATATE–resistant disease. Although DOTATATE can chelate the clinically relevant a-particle–emitting radionuclide 225Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. Methods: We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating 225Ac at room temperature, and assessed its in vitro and in vivo performance. Results: MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. 225Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with 225Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of 225Ac-MACROPATATE than of 225Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that 225Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of 225Ac-MACROPA-TATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with 225Ac-DOTATATE. Conclusion: 225Ac-MACROPATATE and 225Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of 225Ac-MACROPATATE, 225Ac-DOTATATE was deemed the superior agent for targeted a-particle peptide receptor radionuclide therapy.

KW - actinium

KW - neuroendocrine tumors

KW - octreotate

KW - oncology

KW - somatostatin

KW - targeted a-therapy

UR - http://www.scopus.com/inward/record.url?scp=85148939355&partnerID=8YFLogxK

U2 - 10.2967/jnumed.122.264707

DO - 10.2967/jnumed.122.264707

M3 - Article

C2 - 36396453

AN - SCOPUS:85148939355

SN - 0161-5505

VL - 64

SP - 549

EP - 554

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

IS - 4

ER -