JNM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

First published online March 16, 2009, 10.2967/jnumed.108.056903
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow All Versions of this Article:
jnumed.108.056903v1
50/4/625    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Related articles in JNM
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by DeNardo, S. J.
Right arrow Articles by Lam, K. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by DeNardo, S. J.
Right arrow Articles by Lam, K. S.
Journal of Nuclear Medicine Vol. 50 No. 4 625-634
© 2009 by Society of Nuclear Medicine
doi: 10.2967/jnumed.108.056903

Basic Science Investigation

111In-LLP2A-DOTA Polyethylene Glycol–Targeting {alpha}4β1 Integrin: Comparative Pharmacokinetics for Imaging and Therapy of Lymphoid Malignancies

Sally J. DeNardo1, Ruiwu Liu1, Huguette Albrecht1, Arutselvan Natarajan1, Julie L. Sutcliffe2,3, Carolyn Anderson4, Li Peng1, Riccardo Ferdani4, Simon R. Cherry2,3 and Kit S. Lam1

1 Division of Hematology and Oncology, Department of Internal Medicine, UC Davis School of Medicine, Sacramento, California; 2 Department of Biomedical Engineering, University of California, Davis, Davis, California; 3 Center for Molecular and Genomic Imaging, University of California, Davis, Davis, California; and 4 Department of Radiology, Washington University in St. Louis, St. Louis, Missouri

Correspondence: For correspondence or reprints contact: Sally DeNardo, Department of Internal Medicine, UC Davis School of Medicine, University of California, 1508 Alhambra Blvd., Room 3100, Sacramento, CA 95816. E-mail: sjdenardo{at}ucdavis.edu

N-[[4-[[[(2-ethylphenyl)amino]carbonyl]amino]phenyl]acetyl]-N{varepsilon}-6-[(2E)-1-oxo-3-(3-pyridinyl-2-propenyl)]-L-lysyl-L-2-aminohexanedioyl-(1-amino-1-cyclohexane)carboxamide (LLP2A) is a high-affinity, high-specificity peptidomimetic ligand (inhibitory concentration of 50% = 2 pM) that binds the activated {alpha}4β1 integrin found on a variety of malignant lymphoid cell lines. To better determine whether this ligand holds promise for imaging and therapy in lymphoid malignancies, 6 LLP2A derivatives, as LLP2A-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (LLP2A-DOTA) and LLP2A-DOTA-polyethylene glycol (LLP2A-DOTA-PEG), were designed, synthesized, and radiolabeled with 111In. Comparative pharmacokinetic studies in mice with Raji B-cell lymphoma xenografts were then complemented by small-animal PET of the lead molecular LLP2A format using 64Cu-LLP2A-11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (64Cu-LLP2A-CB-TE2A). Methods: LLP2A-DOTA and LLP2A-CB-TE2A were prepared using solid-phase synthesis; LLP2A-DOTA-PEG2,000, LLP2A-DOTA-PEG5,000, LLP2A-DOTA-PEG10,000, (LLP2A-DOTA)2PEG10,000, and (LLP2A-DOTA)4PEG10,000 were prepared by PEGylation. 111In radiolabeling of DOTA and 64Cu radiolabeling of CB-TE2A conjugates yielded 370–1,850 and 3,700–7,400 kBq/µg (10–50 and 100–200 µCi/µg), respectively. The pharmacokinetics of the six 111In radioconjugates were studied in vivo using biodistribution data (4 and 24 h) and whole-body autoradiography (24 h) in mice with Raji tumor xenografts. 64Cu-LLP2A-CB-TE2A was imaged (4 and 24 h) on a small-animal PET scanner in the same mouse model. Results: The highest tumor uptake in pharmacokinetic studies was obtained with LLP2A-DOTA and (LLP2A-DOTA)4-PEG10,000. For 111In-LLP2A-DOTA (1 nM) at 4 and 24 h after injection, ratios of tumor to blood and tumor to nontumor (normal) organ (T/NT) were 8 to 35:1 for all organs or tissue except the spleen, marrow, and kidney, which were between 2:1 and 1:1. Tetravalent (LLP2A-DOTA)4-PEG10,000 (1.1 nM) had tumor uptake similar to the univalent LLP2A-DOTA but higher liver, marrow, and kidney uptake. The excellent T/NT of LLP2A was also demonstrated by small-animal PET with 64Cu-LLP2A-CB-TE2A at both 4 and 24 h after injection; obvious spleen targeting was apparent, but little kidney or liver activity was observed. Conclusion: Of the conjugates investigated, the univalent, non-PEGylated ligand 111In-LLP2A-DOTA exhibited the best T/NT ratios and showed the greatest potential for imaging of {alpha}4β1 in human lymphoma. Furthermore, this univalent non-PEGylated LLP2A format, as 64Cu-LLP2A-CB-TE2A, demonstrated excellent tumor targeting by small-animal PET and warrants further investigation as an agent for the study of {alpha}4β1 expression in human lymphoid malignancies.

Key Words: {alpha}4β • PEGylation • 111In • 64Cu • PET

COPYRIGHT © 2009 by the Society of Nuclear Medicine, Inc.


Related articles in JNM:

This Month in JNM

JNM 2009 50: 11A-12A. [Full Text]  



This article has been cited by other articles:


Home page
 IBMS BoneKEyHome page
J. M. Chirgwin, C. M. Edwards, E. A. Pedersen, Y. Shiozawa, R. S. Taichman, S. I. Park, L. K. McCauley, T. Matsumoto, and M. Abe
Meeting Report from the IX International Meeting on Cancer Induced Bone Disease: October 28-31, 2009 in Arlington, Virginia, USA
IBMS BoneKEy, January 1, 2010; 7(1): 32 - 46.
[Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS
JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY THE JOURNAL OF NUCLEAR MEDICINE
Copyright © 2009 by the Society of Nuclear Medicine.