Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation

Chi Soo Kang; Ningjie Wu; Yunwei Chen; Xiang Sun; Nilantha Bandara; Dijie Liu; Michael R. Lewis; Buck E. Rogers; Hyun Soon Chong

doi:10.1016/j.jinorgbio.2015.10.012

Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation

Chi Soo Kang, Ningjie Wu, Yunwei Chen, Xiang Sun, Nilantha Bandara, Dijie Liu, Michael R. Lewis, Buck E. Rogers, Hyun Soon Chong

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

4 Scopus citations

Abstract

Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with ⁶⁴Cu. In vitro stability and cellular uptake of ⁶⁴Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA-Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with ⁶⁴Cu. N-NE3TA-Tf rapidly bound to ⁶⁴Cu (> 98% radiolabeling efficiency, 1 min, RT), and ⁶⁴Cu-N-NE3TA-Tf remained stable in human serum for 2 days and demonstrated high uptake in PC-3 cancer cells. ⁶⁴Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24 h period. This bifunctional chelate presents highly efficient chelation chemistry with ⁶⁴Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with ⁶⁴Cu for potential use in PET imaging applications.

Original language	English
Pages (from-to)	60-66
Number of pages	7
Journal	Journal of Inorganic Biochemistry
Volume	154
DOIs	https://doi.org/10.1016/j.jinorgbio.2015.10.012
State	Published - Jan 2016

Keywords

Bifunctional chelator
Biodistribution
Copper 64
Radiolabeling
Serum stability
Transferrin

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10.1016/j.jinorgbio.2015.10.012

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Kang, C. S., Wu, N., Chen, Y., Sun, X., Bandara, N., Liu, D., Lewis, M. R., Rogers, B. E., & Chong, H. S. (2016). Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation. Journal of Inorganic Biochemistry, 154, 60-66. https://doi.org/10.1016/j.jinorgbio.2015.10.012

@article{255846abf957445995785c626de23910,

title = "Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation",

abstract = "Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with 64Cu. In vitro stability and cellular uptake of 64Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA-Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with 64Cu. N-NE3TA-Tf rapidly bound to 64Cu (> 98% radiolabeling efficiency, 1 min, RT), and 64Cu-N-NE3TA-Tf remained stable in human serum for 2 days and demonstrated high uptake in PC-3 cancer cells. 64Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24 h period. This bifunctional chelate presents highly efficient chelation chemistry with 64Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with 64Cu for potential use in PET imaging applications.",

keywords = "Bifunctional chelator, Biodistribution, Copper 64, Radiolabeling, Serum stability, Transferrin",

author = "Kang, {Chi Soo} and Ningjie Wu and Yunwei Chen and Xiang Sun and Nilantha Bandara and Dijie Liu and Lewis, {Michael R.} and Rogers, {Buck E.} and Chong, {Hyun Soon}",

note = "Funding Information: This work was partly supported by the National Institutes of Health ( R01 CA136695 ). The authors would like to thank the small animal imaging facility at Washington University School of Medicine for technical assistance in conducting biodistribution studies. We would also like to acknowledge the Isotope Production Group at Washington University for production of 64 Cu. The authors acknowledge Jesse J. Parry and Stephanie Krieger for providing technical assistance with cell lines and xenografted mice, as well as Donald Connor for the preparation of graphic artwork. We also thank the Department of Veterans Affairs, for providing resources and use of facilities at the Harry S. Truman Memorial Veterans' Hospital in Columbia, MO. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2016",

month = jan,

doi = "10.1016/j.jinorgbio.2015.10.012",

language = "English",

volume = "154",

pages = "60--66",

journal = "Journal of Inorganic Biochemistry",

issn = "0162-0134",

}

TY - JOUR

T1 - Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging

T2 - Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation

AU - Kang, Chi Soo

AU - Wu, Ningjie

AU - Chen, Yunwei

AU - Sun, Xiang

AU - Bandara, Nilantha

AU - Liu, Dijie

AU - Lewis, Michael R.

AU - Rogers, Buck E.

AU - Chong, Hyun Soon

N1 - Funding Information: This work was partly supported by the National Institutes of Health ( R01 CA136695 ). The authors would like to thank the small animal imaging facility at Washington University School of Medicine for technical assistance in conducting biodistribution studies. We would also like to acknowledge the Isotope Production Group at Washington University for production of 64 Cu. The authors acknowledge Jesse J. Parry and Stephanie Krieger for providing technical assistance with cell lines and xenografted mice, as well as Donald Connor for the preparation of graphic artwork. We also thank the Department of Veterans Affairs, for providing resources and use of facilities at the Harry S. Truman Memorial Veterans' Hospital in Columbia, MO. Publisher Copyright: © 2015 Elsevier Inc.

PY - 2016/1

Y1 - 2016/1

N2 - Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with 64Cu. In vitro stability and cellular uptake of 64Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA-Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with 64Cu. N-NE3TA-Tf rapidly bound to 64Cu (> 98% radiolabeling efficiency, 1 min, RT), and 64Cu-N-NE3TA-Tf remained stable in human serum for 2 days and demonstrated high uptake in PC-3 cancer cells. 64Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24 h period. This bifunctional chelate presents highly efficient chelation chemistry with 64Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with 64Cu for potential use in PET imaging applications.

AB - Three different polyaminocarboxylate-based bifunctional NE3TA (7-[2-[carboxymethyl)amino]ethyl]-1,4,7-triazacyclononane-1,4-diacetic acid) chelating agents were synthesized for potential use in copper 64-PET imaging applications. The bifunctional chelates were comparatively evaluated using transferrin (Tf) as a model targeting vector that binds to the transferrin receptor overexpressed in many different cancer cells. The transferrin conjugates of the NE3TA-based bifunctional chelates were evaluated for radiolabeling with 64Cu. In vitro stability and cellular uptake of 64Cu-radiolabeled conjugates were evaluated in human serum and prostate (PC-3) cancer cells, respectively. Among the three NE3TA-Tf conjugates tested, N-NE3TA-Tf was identified as the best conjugate for radiolabeling with 64Cu. N-NE3TA-Tf rapidly bound to 64Cu (> 98% radiolabeling efficiency, 1 min, RT), and 64Cu-N-NE3TA-Tf remained stable in human serum for 2 days and demonstrated high uptake in PC-3 cancer cells. 64Cu-N-NE3TA-Tf was shown to have rapid blood clearance and increasing tumor uptake in PC-3 tumor bearing mice over a 24 h period. This bifunctional chelate presents highly efficient chelation chemistry with 64Cu under mild condition that can be applied for radiolabeling of various tumor-specific biomolecules with 64Cu for potential use in PET imaging applications.

KW - Bifunctional chelator

KW - Biodistribution

KW - Copper 64

KW - Radiolabeling

KW - Serum stability

KW - Transferrin

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U2 - 10.1016/j.jinorgbio.2015.10.012

DO - 10.1016/j.jinorgbio.2015.10.012

M3 - Article

C2 - 26583705

AN - SCOPUS:84946763535

SN - 0162-0134

VL - 154

SP - 60

EP - 66

JO - Journal of Inorganic Biochemistry

JF - Journal of Inorganic Biochemistry

ER -

Transferrin conjugates of triazacyclononane-based bifunctional NE3TA chelates for PET imaging: Synthesis, Cu-64 radiolabeling, and in vitro and in vivo evaluation

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