skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice

Abstract

The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100 μg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500 μg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels of plasma cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions. - Highlights: • Intravenous administration of ESTA was well tolerated. • ESTA up to 500 μg does not cause hematologic, organs, and immunologic responses. • ESTA-mediated hepatic abnormality was considered minor.

Authors:
;  [1];  [2]; ; ;  [1]; ;  [2]; ; ;  [1];  [3];  [4];  [2];  [1]
  1. Stephenson Cancer Center, University of Oklahoma Health Sciences Center, 975 NE, 10th, Oklahoma City, OK 73104 (United States)
  2. Institute of Molecular Medicine, Department of NanoMedicine and Biomedical Engineering, University of Texas Health Science Center at Houston, 1825 Hermann Pressler, Houston, TX 77030 (United States)
  3. Thomas Jefferson University, 1020 Locust St, Philadelphia, PA 19107 (United States)
  4. John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ 07601 (United States)
Publication Date:
OSTI Identifier:
22465808
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 287; Journal Issue: 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; DOSES; INTRAVENOUS INJECTION; LIVER; LYMPHOKINES; MAMMARY GLANDS; METASTASES; MICE; NEOPLASMS; SAFETY ANALYSIS; TOXICITY

Citation Formats

Kang, Shin-Ae, Tsolmon, Bilegtsaikhan, Mann, Aman P., Zheng, Wei, Zhao, Lichao, Zhao, Yan Daniel, Volk, David E., Lokesh, Ganesh L.-R., Morris, Lynsie, Gupta, Vineet, Razaq, Wajeeha, Rui, Hallgeir, Suh, K. Stephen, Gorenstein, David G., and Tanaka, Takemi, E-mail: takemi-tanaka@ouhsc.edu. Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice. United States: N. p., 2015. Web. doi:10.1016/J.TAAP.2015.05.011.
Kang, Shin-Ae, Tsolmon, Bilegtsaikhan, Mann, Aman P., Zheng, Wei, Zhao, Lichao, Zhao, Yan Daniel, Volk, David E., Lokesh, Ganesh L.-R., Morris, Lynsie, Gupta, Vineet, Razaq, Wajeeha, Rui, Hallgeir, Suh, K. Stephen, Gorenstein, David G., & Tanaka, Takemi, E-mail: takemi-tanaka@ouhsc.edu. Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice. United States. doi:10.1016/J.TAAP.2015.05.011.
Kang, Shin-Ae, Tsolmon, Bilegtsaikhan, Mann, Aman P., Zheng, Wei, Zhao, Lichao, Zhao, Yan Daniel, Volk, David E., Lokesh, Ganesh L.-R., Morris, Lynsie, Gupta, Vineet, Razaq, Wajeeha, Rui, Hallgeir, Suh, K. Stephen, Gorenstein, David G., and Tanaka, Takemi, E-mail: takemi-tanaka@ouhsc.edu. Sat . "Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice". United States. doi:10.1016/J.TAAP.2015.05.011.
@article{osti_22465808,
title = {Safety evaluation of intravenously administered mono-thioated aptamer against E-selectin in mice},
author = {Kang, Shin-Ae and Tsolmon, Bilegtsaikhan and Mann, Aman P. and Zheng, Wei and Zhao, Lichao and Zhao, Yan Daniel and Volk, David E. and Lokesh, Ganesh L.-R. and Morris, Lynsie and Gupta, Vineet and Razaq, Wajeeha and Rui, Hallgeir and Suh, K. Stephen and Gorenstein, David G. and Tanaka, Takemi, E-mail: takemi-tanaka@ouhsc.edu},
abstractNote = {The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100 μg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500 μg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels of plasma cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-γ, and TNF-α) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions. - Highlights: • Intravenous administration of ESTA was well tolerated. • ESTA up to 500 μg does not cause hematologic, organs, and immunologic responses. • ESTA-mediated hepatic abnormality was considered minor.},
doi = {10.1016/J.TAAP.2015.05.011},
journal = {Toxicology and Applied Pharmacology},
number = 1,
volume = 287,
place = {United States},
year = {Sat Aug 15 00:00:00 EDT 2015},
month = {Sat Aug 15 00:00:00 EDT 2015}
}
  • Polymethacrylic nanospheres (mean diameter 0.25-0.30 microns), prepared by aqueous emulsion copolymerization, were developed as a new site-specific drug delivery system. The nanoparticles were labeled either with indium-111 or iodine-125, and after a single iv injection of labeled particles into mice, their blood clearance and organ distribution were analyzed. A rapid clearance of {sup 111}In-labeled nanoparticles from the blood circulation to the mononuclear phagocyte system (MPS) was visualized using external scintigraphic imaging. From 10 to 60 min, radioactivity measurements in blood and organs (liver, spleen, kidneys, lungs, heart) showed that the {sup 125}I-labeled nanospheres were rapidly removed from the bloodstream (distributionmore » half-life approximately 3-5 min) and mainly deposited in the liver (60% of the administered dose, 10 min after administration). Up to 1 h, radioactivity in heart and lungs remained insignificant, while in the kidneys, radioactivity levels increased from 8 to 11%.« less
  • Groups of male CD-1 mice (n = 12/group) were injected intraperitoneally (IP) with 5 g ethanol/kg of body weight. After loss of righting reflex, they were given vehicle or one of 2-3 doses of reputed or potential antagonists of ethanol intravenously (IV). Sleep time was measured from loss to return of righting reflex. Mean sleep time (MST) was increased significantly by a large dose of dl-amphetamine and by 4-aminopyridine. Significant increases were also produced by small and large doses of aminophylline and by yohimbine. MST was not altered significantly by small and medium doses of dl-amphetamine, a medium dose ofmore » aminophylline, or by any doses of naloxone, thyrotropin-releasing hormone, propranolol, physostigmine, doxapram, or Ro 15-4513. When Ro 15-4513 was given IP 15 minutes before ethanol (n = 6/group), onset and duration of narcosis were not altered. None of the compounds tested was an effective IV antidote for deep ethanol narcosis because of drug side effects, toxicity, prolongation of MST, or insufficient shortening of MST. 36 references, 1 table.« less
  • Highlights: Black-Right-Pointing-Pointer There is rising concern regarding the potential health risks of nanomaterials. Black-Right-Pointing-Pointer Few studies have investigated the effect of nanomaterials on the reproductive system. Black-Right-Pointing-Pointer Here, we evaluated the intra-testicular distribution of nanosilica particles. Black-Right-Pointing-Pointer We showed that nanosilica particles can penetrate the blood-testis barrier. Black-Right-Pointing-Pointer These data provide basic information on ways to create safer nanomaterials. -- Abstract: Amorphous nanosilica particles (nSP) are being utilized in an increasing number of applications such as medicine, cosmetics, and foods. The reduction of the particle size to the nanoscale not only provides benefits to diverse scientific fields but also posesmore » potential risks. Several reports have described the in vivo and in vitro toxicity of nSP, but few studies have examined their effects on the male reproductive system. The aim of this study was to evaluate the testicular distribution and histologic effects of systemically administered nSP. Mice were injected intravenously with nSP with diameters of 70 nm (nSP70) or conventional microsilica particles with diameters of 300 nm (nSP300) on two consecutive days. The intratesticular distribution of these particles 24 h after the second injection was analyzed by transmission electron microscopy. nSP70 were detected within sertoli cells and spermatocytes, including in the nuclei of spermatocytes. No nSP300 were observed in the testis. Next, mice were injected intravenously with 0.4 or 0.8 mg nSP70 every other day for a total of four administrations. Testes were harvested 48 h and 1 week after the last injection and stained with hematoxylin-eosin for histologic analysis. Histologic findings in the testes of nSP70-treated mice did not differ from those of control mice. Taken together, our results suggest that nSP70 can penetrate the blood-testis barrier and the nuclear membranes of spermatocytes without producing apparent testicular injury.« less