Phosphatidylserine-targeted bimodal liposomal nanoparticles for in vivo imaging of breast cancer in mice.
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 9.4T, T2-weighted MRI detected drastic reduction on signal intensity and T2 values of tumors at 24h. 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 24h. 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.
Radiology, UT Southwestern Medical Center, Dallas, USA.
Liang
L
Zhang
Radiology, UT Southwestern Medical Center, Dallas, USA.
Heling
H
Zhou
Pharmacology, UT Southwestern Medical Center, Dallas, USA.
Olivier
O
Belzile
Pharmacology, UT Southwestern Medical Center, Dallas, USA.
Philip
P
Thorpe
Radiology, UT Southwestern Medical Center, Dallas, USA. Electronic address: Dawen.Zhao@UTSouthwestern.edu.
Dawen
D
Zhao
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000737:chemistry; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D008081:Liposomes; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000737:chemistry; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000175:diagnosis* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging / Q000379:methods*; D010718:Phosphatidylserines / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D003287:Contrast Media; D008081:Liposomes; D058185:Magnetite Nanoparticles; D010718:Phosphatidylserines
Bimodal liposomal nanoprobe; Breast cancer; Magnetic resonance imaging (MRI); Near-infrared optical imaging; Phosphatidylserine (PS); Tumor vasculature