Development of 111in-labeled liposomes for vulnerable atherosclerotic plaque imaging

Mikako Ogawa, Izumi O. Umeda, Mutsumi Kosugi, Ayumi Kawai, Yuka Hamaya, Misato Takashima, Hongxia Yin, Takayuki Kudoh, Masaharu Seno, Yasuhiro Magata

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Macrophage infiltration is a common characteristic feature of atherosclerotic-vulnerable plaques. Macrophages recognize phosphatidylserine (PS) exposed on the surface of apoptotic cells, which triggers the engulfment of the apoptotic cells by macrophages through phagocytosis. In this study, we prepared radiolabeled PS liposomes for detection of vulnerable plaques. Methods: PS liposomes were prepared by lipid film hydration. Phosphatidylcholine (PC) liposomes were prepared as controls. Liposomes (100 or 200 nm) were generated by an extruder to produce PS100, PS200, PC100, and PC200 liposomes. These were then radiolabeled by encapsulating 111In-nitrilotriacetic acid using an active-loading method. 111In liposomes were incubated with cultured macrophages for 2 h, and the uptake level was measured. For biodistribution studies, the 111In liposomes were injected intravenously into ddY mice. In addition, the 111In liposomes were injected into apolipoprotein E-deficient (apoE-/-) mice, and the aortas were harvested for autoradiography and oil red O staining. For SPECT imaging, 111In liposomes were injected intravenously into Watanabe heritable hyperlipidemic rabbits and scanned 48 h after injection. Results: The radiochemical yields were greater than 95% for all the prepared 111In liposomes. The level of in vitro uptake by macrophages was 60.5, 14.7, 32.0, and 14.4 percentage injected dose per milligram of protein for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. In biodistribution studies, high spleen uptake was seen with PC liposomes. Liver uptake was high for all liposomes but was lowest with 111In-PS200. The blood half-lives were 3.2, 22.0, 3.6, and 7.4 min for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The distribution of 111In-labeled PS liposomes into atherosclerotic regions determined by autoradiography was well matched with the results of oil red O staining in apoE-/- mice. The target-to-nontarget ratios were 2.62, 2.23, 3.27, and 2.51 for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The aorta was successfully visualized by SPECT at 48 h after 111In-labeled PS liposome injection; however, high liver uptake was also observed. Discussion: From the in vitro uptake study, it has been demonstrated that macrophage targeting was accomplished by PS modification. Also, an atherosclerotic region was successfully detected by 111In-PS200 in apoE-/- mice and Watanabe heritable hyperlipidemic rabbits in vivo. Liposome modification to obtain slower blood clearance and lower liver uptake would be required to improve the SPECT images.

Original languageEnglish
Pages (from-to)115-120
Number of pages6
JournalJournal of Nuclear Medicine
Volume55
Issue number1
DOIs
Publication statusPublished - Jan 1 2014

Fingerprint

Atherosclerotic Plaques
Liposomes
Phosphatidylserines
Macrophages
Apolipoproteins E
Single-Photon Emission-Computed Tomography
Autoradiography
Phosphatidylcholines
Aorta
Liver
Nitrilotriacetic Acid
Staining and Labeling
Rabbits
Injections
Phagocytosis

Keywords

  • Atherosclerosis
  • Liposome
  • Phosphatidylserine
  • SPECT

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Medicine(all)

Cite this

Ogawa, M., Umeda, I. O., Kosugi, M., Kawai, A., Hamaya, Y., Takashima, M., ... Magata, Y. (2014). Development of 111in-labeled liposomes for vulnerable atherosclerotic plaque imaging. Journal of Nuclear Medicine, 55(1), 115-120. https://doi.org/10.2967/jnumed.113.123158

Development of 111in-labeled liposomes for vulnerable atherosclerotic plaque imaging. / Ogawa, Mikako; Umeda, Izumi O.; Kosugi, Mutsumi; Kawai, Ayumi; Hamaya, Yuka; Takashima, Misato; Yin, Hongxia; Kudoh, Takayuki; Seno, Masaharu; Magata, Yasuhiro.

In: Journal of Nuclear Medicine, Vol. 55, No. 1, 01.01.2014, p. 115-120.

Research output: Contribution to journalArticle

Ogawa, M, Umeda, IO, Kosugi, M, Kawai, A, Hamaya, Y, Takashima, M, Yin, H, Kudoh, T, Seno, M & Magata, Y 2014, 'Development of 111in-labeled liposomes for vulnerable atherosclerotic plaque imaging', Journal of Nuclear Medicine, vol. 55, no. 1, pp. 115-120. https://doi.org/10.2967/jnumed.113.123158
Ogawa, Mikako ; Umeda, Izumi O. ; Kosugi, Mutsumi ; Kawai, Ayumi ; Hamaya, Yuka ; Takashima, Misato ; Yin, Hongxia ; Kudoh, Takayuki ; Seno, Masaharu ; Magata, Yasuhiro. / Development of 111in-labeled liposomes for vulnerable atherosclerotic plaque imaging. In: Journal of Nuclear Medicine. 2014 ; Vol. 55, No. 1. pp. 115-120.
@article{d02696a098c248e29119951cee76e7e0,
title = "Development of 111in-labeled liposomes for vulnerable atherosclerotic plaque imaging",
abstract = "Macrophage infiltration is a common characteristic feature of atherosclerotic-vulnerable plaques. Macrophages recognize phosphatidylserine (PS) exposed on the surface of apoptotic cells, which triggers the engulfment of the apoptotic cells by macrophages through phagocytosis. In this study, we prepared radiolabeled PS liposomes for detection of vulnerable plaques. Methods: PS liposomes were prepared by lipid film hydration. Phosphatidylcholine (PC) liposomes were prepared as controls. Liposomes (100 or 200 nm) were generated by an extruder to produce PS100, PS200, PC100, and PC200 liposomes. These were then radiolabeled by encapsulating 111In-nitrilotriacetic acid using an active-loading method. 111In liposomes were incubated with cultured macrophages for 2 h, and the uptake level was measured. For biodistribution studies, the 111In liposomes were injected intravenously into ddY mice. In addition, the 111In liposomes were injected into apolipoprotein E-deficient (apoE-/-) mice, and the aortas were harvested for autoradiography and oil red O staining. For SPECT imaging, 111In liposomes were injected intravenously into Watanabe heritable hyperlipidemic rabbits and scanned 48 h after injection. Results: The radiochemical yields were greater than 95{\%} for all the prepared 111In liposomes. The level of in vitro uptake by macrophages was 60.5, 14.7, 32.0, and 14.4 percentage injected dose per milligram of protein for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. In biodistribution studies, high spleen uptake was seen with PC liposomes. Liver uptake was high for all liposomes but was lowest with 111In-PS200. The blood half-lives were 3.2, 22.0, 3.6, and 7.4 min for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The distribution of 111In-labeled PS liposomes into atherosclerotic regions determined by autoradiography was well matched with the results of oil red O staining in apoE-/- mice. The target-to-nontarget ratios were 2.62, 2.23, 3.27, and 2.51 for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The aorta was successfully visualized by SPECT at 48 h after 111In-labeled PS liposome injection; however, high liver uptake was also observed. Discussion: From the in vitro uptake study, it has been demonstrated that macrophage targeting was accomplished by PS modification. Also, an atherosclerotic region was successfully detected by 111In-PS200 in apoE-/- mice and Watanabe heritable hyperlipidemic rabbits in vivo. Liposome modification to obtain slower blood clearance and lower liver uptake would be required to improve the SPECT images.",
keywords = "Atherosclerosis, Liposome, Phosphatidylserine, SPECT",
author = "Mikako Ogawa and Umeda, {Izumi O.} and Mutsumi Kosugi and Ayumi Kawai and Yuka Hamaya and Misato Takashima and Hongxia Yin and Takayuki Kudoh and Masaharu Seno and Yasuhiro Magata",
year = "2014",
month = "1",
day = "1",
doi = "10.2967/jnumed.113.123158",
language = "English",
volume = "55",
pages = "115--120",
journal = "Journal of Nuclear Medicine",
issn = "0161-5505",
publisher = "Society of Nuclear Medicine Inc.",
number = "1",

}

TY - JOUR

T1 - Development of 111in-labeled liposomes for vulnerable atherosclerotic plaque imaging

AU - Ogawa, Mikako

AU - Umeda, Izumi O.

AU - Kosugi, Mutsumi

AU - Kawai, Ayumi

AU - Hamaya, Yuka

AU - Takashima, Misato

AU - Yin, Hongxia

AU - Kudoh, Takayuki

AU - Seno, Masaharu

AU - Magata, Yasuhiro

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Macrophage infiltration is a common characteristic feature of atherosclerotic-vulnerable plaques. Macrophages recognize phosphatidylserine (PS) exposed on the surface of apoptotic cells, which triggers the engulfment of the apoptotic cells by macrophages through phagocytosis. In this study, we prepared radiolabeled PS liposomes for detection of vulnerable plaques. Methods: PS liposomes were prepared by lipid film hydration. Phosphatidylcholine (PC) liposomes were prepared as controls. Liposomes (100 or 200 nm) were generated by an extruder to produce PS100, PS200, PC100, and PC200 liposomes. These were then radiolabeled by encapsulating 111In-nitrilotriacetic acid using an active-loading method. 111In liposomes were incubated with cultured macrophages for 2 h, and the uptake level was measured. For biodistribution studies, the 111In liposomes were injected intravenously into ddY mice. In addition, the 111In liposomes were injected into apolipoprotein E-deficient (apoE-/-) mice, and the aortas were harvested for autoradiography and oil red O staining. For SPECT imaging, 111In liposomes were injected intravenously into Watanabe heritable hyperlipidemic rabbits and scanned 48 h after injection. Results: The radiochemical yields were greater than 95% for all the prepared 111In liposomes. The level of in vitro uptake by macrophages was 60.5, 14.7, 32.0, and 14.4 percentage injected dose per milligram of protein for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. In biodistribution studies, high spleen uptake was seen with PC liposomes. Liver uptake was high for all liposomes but was lowest with 111In-PS200. The blood half-lives were 3.2, 22.0, 3.6, and 7.4 min for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The distribution of 111In-labeled PS liposomes into atherosclerotic regions determined by autoradiography was well matched with the results of oil red O staining in apoE-/- mice. The target-to-nontarget ratios were 2.62, 2.23, 3.27, and 2.51 for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The aorta was successfully visualized by SPECT at 48 h after 111In-labeled PS liposome injection; however, high liver uptake was also observed. Discussion: From the in vitro uptake study, it has been demonstrated that macrophage targeting was accomplished by PS modification. Also, an atherosclerotic region was successfully detected by 111In-PS200 in apoE-/- mice and Watanabe heritable hyperlipidemic rabbits in vivo. Liposome modification to obtain slower blood clearance and lower liver uptake would be required to improve the SPECT images.

AB - Macrophage infiltration is a common characteristic feature of atherosclerotic-vulnerable plaques. Macrophages recognize phosphatidylserine (PS) exposed on the surface of apoptotic cells, which triggers the engulfment of the apoptotic cells by macrophages through phagocytosis. In this study, we prepared radiolabeled PS liposomes for detection of vulnerable plaques. Methods: PS liposomes were prepared by lipid film hydration. Phosphatidylcholine (PC) liposomes were prepared as controls. Liposomes (100 or 200 nm) were generated by an extruder to produce PS100, PS200, PC100, and PC200 liposomes. These were then radiolabeled by encapsulating 111In-nitrilotriacetic acid using an active-loading method. 111In liposomes were incubated with cultured macrophages for 2 h, and the uptake level was measured. For biodistribution studies, the 111In liposomes were injected intravenously into ddY mice. In addition, the 111In liposomes were injected into apolipoprotein E-deficient (apoE-/-) mice, and the aortas were harvested for autoradiography and oil red O staining. For SPECT imaging, 111In liposomes were injected intravenously into Watanabe heritable hyperlipidemic rabbits and scanned 48 h after injection. Results: The radiochemical yields were greater than 95% for all the prepared 111In liposomes. The level of in vitro uptake by macrophages was 60.5, 14.7, 32.0, and 14.4 percentage injected dose per milligram of protein for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. In biodistribution studies, high spleen uptake was seen with PC liposomes. Liver uptake was high for all liposomes but was lowest with 111In-PS200. The blood half-lives were 3.2, 22.0, 3.6, and 7.4 min for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The distribution of 111In-labeled PS liposomes into atherosclerotic regions determined by autoradiography was well matched with the results of oil red O staining in apoE-/- mice. The target-to-nontarget ratios were 2.62, 2.23, 3.27, and 2.51 for 111In-PS100, 111In-PC100, 111In-PS200, and 111In-PC200, respectively. The aorta was successfully visualized by SPECT at 48 h after 111In-labeled PS liposome injection; however, high liver uptake was also observed. Discussion: From the in vitro uptake study, it has been demonstrated that macrophage targeting was accomplished by PS modification. Also, an atherosclerotic region was successfully detected by 111In-PS200 in apoE-/- mice and Watanabe heritable hyperlipidemic rabbits in vivo. Liposome modification to obtain slower blood clearance and lower liver uptake would be required to improve the SPECT images.

KW - Atherosclerosis

KW - Liposome

KW - Phosphatidylserine

KW - SPECT

UR - http://www.scopus.com/inward/record.url?scp=84894786216&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84894786216&partnerID=8YFLogxK

U2 - 10.2967/jnumed.113.123158

DO - 10.2967/jnumed.113.123158

M3 - Article

C2 - 24337605

AN - SCOPUS:84894786216

VL - 55

SP - 115

EP - 120

JO - Journal of Nuclear Medicine

JF - Journal of Nuclear Medicine

SN - 0161-5505

IS - 1

ER -