Targeting of primary breast cancers and metastases in a transgenic mouse model using rationally designed multifunctional SPIONs.
Breast cancer remains one of the most prevalent and lethal malignancies in women. The inability to diagnose small volume metastases early has limited effective treatment of stage 4 breast cancer. Here we report the rational development and use of a multifunctional superparamagnetic iron oxide nanoparticle (SPION) for targeting metastatic breast cancer in a transgenic mouse model and imaging with magnetic resonance (MR). SPIONs coated with a copolymer of chitosan and polyethylene glycol (PEG) were labeled with a fluorescent dye for optical detection and conjugated with a monoclonal antibody against the neu receptor (NP-neu). SPIONs labeled with mouse IgG were used as a nontargeting control (NP-IgG). These SPIONs had desirable physiochemical properties for in vivo applications such as near neutral zeta potential and hydrodynamic size around 40 nm and were highly stable in serum containing medium. Only NP-neu showed high uptake in neu expressing mouse mammary carcinoma (MMC) cells which was reversed by competing free neu antibody, indicating their specificity to the neu antigen. In vivo, NP-neu was able to tag primary breast tumors and significantly, only NP-neu bound to spontaneous liver, lung, and bone marrow metastases in a transgenic mouse model of metastatic breast cancer, highlighting the necessity of targeting for delivery to metastatic disease. The SPIONs provided significant contrast enhancement in MR images of primary breast tumors; thus, they have the potential for MRI detection of micrometastases and provide an excellent platform for further development of an efficient metastatic breast cancer therapy.
Department of Materials Science & Engineering, University of Washington, Seattle, Washington 98195, USA.
Forrest M
FM
Kievit
Zachary R
ZR
Stephen
Omid
O
Veiseh
Hamed
H
Arami
Tingzhong
T
Wang
Vy P
VP
Lai
James O
JO
Park
Richard G
RG
Ellenbogen
Mary L
ML
Disis
Miqin
M
Zhang
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D055598:Chemical Phenomena; D048271:Chitosan / Q000737:chemistry; D004195:Disease Models, Animal; D015195:Drug Design; D008279:Magnetic Resonance Imaging; D058185:Magnetite Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D011092:Polyethylene Glycols / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D013379:Substrate Specificity
D000911:Antibodies, Monoclonal; D048271:Chitosan; D058185:Magnetite Nanoparticles; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases