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Title: Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine

Abstract

Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. In conclusion, the results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.

Authors:
 [1];  [2];  [3];  [4]
+ Show Author Affiliations
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Univ. of New Mexico Health Science Center, Albuquerque, NM (United States)
  3. Univ. of Missouri-Columbia, Columbia, MO (United States)
  4. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Univ. of New Mexico Health Science Center, Albuquerque, NM (United States)
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1240731
Report Number(s):
LA-UR-16-20619
Journal ID: ISSN 2227-9059; BIOMID; PII: biomedicines4010001
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Biomedicines
Additional Journal Information:
Journal Volume: 4; Journal Issue: 1; Journal ID: ISSN 2227-9059
Publisher:
MDPI
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 07 ISOTOPE AND RADIATION SOURCES; 77 NANOSCIENCE AND NANOTECHNOLOGY; 38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; 62 RADIOLOGY AND NUCLEAR MEDICINE; Promethium-149; Trastuzumab; polyethylenimine; radiotherapy; targeted therapy; Actinium-225

Citation Formats

Fitzsimmons, Jonathan, Nayak, Tapan, Cutler, Cathy, and Atcher, Robert. Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine. United States: N. p., 2015. Web. doi:10.3390/biomedicines4010001.
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Fitzsimmons, Jonathan, Nayak, Tapan, Cutler, Cathy, & Atcher, Robert. Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine. United States. https://doi.org/10.3390/biomedicines4010001
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Fitzsimmons, Jonathan, Nayak, Tapan, Cutler, Cathy, and Atcher, Robert. Wed . "Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine". United States. https://doi.org/10.3390/biomedicines4010001. https://www.osti.gov/servlets/purl/1240731.
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@article{osti_1240731,
title = {Synthesis and preliminary biological evaluations of fluorescent or 149Promethium labeled Trastuzumab-polyethylenimine},
author = {Fitzsimmons, Jonathan and Nayak, Tapan and Cutler, Cathy and Atcher, Robert},
abstractNote = {Radioimmunotherapy utilize a targeting antibody coupled to a therapeutic isotope to target and treat a tumor or disease. In this study we examine the synthesis and cell binding of a polymer scaffold containing a radiotherapeutic isotope and a targeting antibody. Methods: The multistep synthesis of a fluorescent or 149Promethium-labeled Trastuzumab-polyethyleneimine (PEI), Trastuzumab, or PEI is described. In vitro uptake, internalization and/or the binding affinity to the Her2/neu expressing human breast adenocarcinoma SKBr3 cells was investigated with the labeled compounds. Fluorescent-labeled Trastuzumab-PEI was internalized more into cells at 2 and 18 h than fluorescent-labeled Trastuzumab or PEI. The fluorescent-labeled Trastuzumab was concentrated on the cell surface at 2 and 18 h and the labeled PEI had minimal uptake. DOTA-PEI was prepared and contained an average of 16 chelates per PEI; the compound was radio-labeled with 149Promethium and conjugated to Trastuzumab. The purified 149Pm-DOTA-PEI-Trastuzumab had a radiochemical purity of 96.7% and a specific activity of 0.118 TBq/g. The compound demonstrated a dissociation constant for the Her2/neu receptor of 20.30 ± 6.91 nM. In conclusion, the results indicate the DOTA-PEI-Trastuzumab compound has potential as a targeted therapeutic carrier, and future in vivo studies should be performed.},
doi = {10.3390/biomedicines4010001},
journal = {Biomedicines},
number = 1,
volume = 4,
place = {United States},
year = {Wed Dec 30 00:00:00 EST 2015},
month = {Wed Dec 30 00:00:00 EST 2015}
}
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https://doi.org/10.3390/biomedicines4010001
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