Image-guided breast tumor therapy using a small interfering RNA nanodrug.
Iron oxide nanoparticles offer a feasible tool for combined imaging and delivery of small interfering RNA (siRNA) to tumors, stimulating active interest in exploring different imaging and delivery platforms suitable for detection by a variety of modalities. In this study, we describe the synthesis and testing of a tumor-targeted nanodrug (MN-EPPT-siBIRC5) that is designed to specifically shuttle siRNA to human breast tumors. The nanodrug binds the tumor-specific antigen uMUC-1, which is found in >90% of human breast adenocarcinomas. MN-EPPT-siBIRC5 consists of superparamagnetic iron oxide nanoparticles [for magnetic resonance imaging (MRI)], the dye Cy 5.5 (for near-IR optical imaging), peptides (EPPT) that specifically target uMUC-1, and a synthetic siRNA that targets the tumor-specific antiapoptotic gene BIRC5. Nanodrug uptake by human breast adenocarcinoma cells resulted in a significant downregulation of BIRC5. Following i.v. delivery into subcutaneous mouse models of breast cancer, the nanodrug showed a preferential tumor uptake, which could be visualized by MRI and near-IR optical imaging. Furthermore, MRI could be used to quantitatively monitor nanodrug bioavailability in the tumor tissue throughout the course of treatment. Intravenous injection of the agent once a week over 2 weeks resulted in the induction of considerable levels of necrosis and apoptosis in the tumors, translating into a significant decrease in tumor growth rate. Our strategy permits the simultaneous tumor-specific delivery of siRNA to tumors and the imaging of the delivery process. More generally, it illustrates the potential to apply this approach to many human cancer studies, including for basic tumor biology and therapy.
Kumar
Mohanraja
M
Molecular Imaging Laboratory, MGH/HST Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02129, USA.
Yigit
Mehmet
M
Dai
Guangping
G
Moore
Anna
A
Medarova
Zdravka
Z
D000595:Amino Acid Sequence; D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D002232:Carbocyanines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D005260:Female; D005290:Ferric Compounds / Q000008:administration & dosage / Q000737:chemistry; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
C107489:BIRC5 protein, human; C098793:CY5.5 cyanine dye; D002232:Carbocyanines; D005290:Ferric Compounds; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010455:Peptides; D034741:RNA, Small Interfering; D000077022:Survivin; C000499:ferric oxide