TY - JOUR
T1 - Phosphatidylserine-targeted bimodal liposomal nanoparticles for in vivo imaging of breast cancer in mice
AU - Zhang, Liang
AU - Zhou, Heling
AU - Belzile, Olivier
AU - Thorpe, Philip
AU - Zhao, Dawen
N1 - Funding Information:
This work was supported in part by DOD W81XWH-12-1-0317 . Imaging was conducted by DOE grant DE-FG02-05CH11280 , NIH BTRP P41-RR02584 , NCI U24 CA126608 and NCI 1P30 CA142543 . Dr. Philip Thorpe was a key investigator being both on discovering exposed PS on tumor vasculature and development of a series of PS-targeting antibodies. Sadly he passed away shortly after the completion of the study. We thank Peregrine Pharmaceuticals Inc., Tustin, CA, for the provision of PGN635 antibody. We are grateful to Drs. Yiguang Wang, Gang Huang and Jinming Gao for technical and collegial support.
PY - 2014/6/10
Y1 - 2014/6/10
N2 - Phosphatidylserine (PS) that is normally constrained to the inner plasma membrane becomes exposed on the surface of endothelial cells (ECs) in tumor vasculature. In the present study, we report the development of a novel tumor vasculature-targeted liposomal nanoprobe by conjugating a human monoclonal antibody, PGN635 that specifically targets PS to polyethylene glycol-coated liposomes. MR contrast, superparamagnetic iron oxide nanoparticles (SPIO) were packed into the core of liposomes, while near-infrared dye, DiR was incorporated into the lipophilic bilayer. The liposomal nanoprobe PGN-L-IO/DiR was fully characterized, and its binding specificity and subsequent internalization into PS-exposed vascular ECs was confirmed by in vitro MRI and histological staining. In vivo longitudinal MRI and optical imaging were performed after i.v. injection of the liposomal nanoprobes into mice bearing breast MDA-MB231 tumors. At 9.4 T, T2-weighted MRI detected drastic reduction on signal intensity and T2 values of tumors at 24 h. Ionizing radiation significantly increased PS exposure on tumor vascular ECs, resulting in a further MRI signal loss of tumors. Concurrent with MRI, optical imaging revealed a clear tumor contrast at 24 h. Intriguingly, PGN-L-IO/DiR exhibited distinct pharmacokinetics and biodistribution with significantly reduced accumulations in liver or spleen. Localization of PGN-L-IO/DiR to tumor was antigen specific, since a control probe of irrelevant specificity showed minimal accumulation in the tumors. Our studies indicate that PS-targeted liposomes may provide a useful platform for tumor-targeted delivery of imaging contrast agents or potentially anti-cancer drugs for cancer theranostics.
AB - Phosphatidylserine (PS) that is normally constrained to the inner plasma membrane becomes exposed on the surface of endothelial cells (ECs) in tumor vasculature. In the present study, we report the development of a novel tumor vasculature-targeted liposomal nanoprobe by conjugating a human monoclonal antibody, PGN635 that specifically targets PS to polyethylene glycol-coated liposomes. MR contrast, superparamagnetic iron oxide nanoparticles (SPIO) were packed into the core of liposomes, while near-infrared dye, DiR was incorporated into the lipophilic bilayer. The liposomal nanoprobe PGN-L-IO/DiR was fully characterized, and its binding specificity and subsequent internalization into PS-exposed vascular ECs was confirmed by in vitro MRI and histological staining. In vivo longitudinal MRI and optical imaging were performed after i.v. injection of the liposomal nanoprobes into mice bearing breast MDA-MB231 tumors. At 9.4 T, T2-weighted MRI detected drastic reduction on signal intensity and T2 values of tumors at 24 h. Ionizing radiation significantly increased PS exposure on tumor vascular ECs, resulting in a further MRI signal loss of tumors. Concurrent with MRI, optical imaging revealed a clear tumor contrast at 24 h. Intriguingly, PGN-L-IO/DiR exhibited distinct pharmacokinetics and biodistribution with significantly reduced accumulations in liver or spleen. Localization of PGN-L-IO/DiR to tumor was antigen specific, since a control probe of irrelevant specificity showed minimal accumulation in the tumors. Our studies indicate that PS-targeted liposomes may provide a useful platform for tumor-targeted delivery of imaging contrast agents or potentially anti-cancer drugs for cancer theranostics.
KW - Bimodal liposomal nanoprobe
KW - Breast cancer
KW - Magnetic resonance imaging (MRI)
KW - Near-infrared optical imaging
KW - Phosphatidylserine (PS)
KW - Tumor vasculature
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U2 - 10.1016/j.jconrel.2014.03.043
DO - 10.1016/j.jconrel.2014.03.043
M3 - Article
C2 - 24698945
AN - SCOPUS:84898647966
SN - 0168-3659
VL - 183
SP - 114
EP - 123
JO - Journal of Controlled Release
JF - Journal of Controlled Release
IS - 1
ER -