Inhibition of tumor-cell invasion with chlorotoxin-bound superparamagnetic nanoparticles.
Nanoparticles have been investigated as drug delivery vehicles, contrast agents, and multifunctional devices for patient care. Current nanoparticle-based therapeutic strategies for cancer treatment are mainly based on delivery of chemotherapeutic agents to induce apoptosis or DNA/siRNA to regulate oncogene expression. Here, a nanoparticle system that demonstrates an alternative approach to the treatment of cancers through the inhibition of cell invasion, while serving as a magnetic resonance and optical imaging contrast agent, is presented. The nanoparticle comprises an iron oxide nanoparticle core conjugated with an amine-functionalized poly(ethylene glycol) silane and a small peptide, chlorotoxin (CTX), which enables the tumor cell-specific binding of the nanoparticle. It is shown that the nanoparticle exhibits substantially enhanced cellular uptake and an invasion inhibition rate of approximately 98% compared to unbound CTX ( approximately 45%). Significantly, the investigation from flow cytometry analysis, transmission electron microscopy, and fluorescent imaging reveals that the CTX-enabled nanoparticles deactivated the membrane-bound matrix metalloproteinase 2 (MMP-2) and induced increased internalization of lipid rafts that contain surface-expressed MMP-2 and volume-regulating ion channels through receptor-mediated endocytosis, leading to enhanced prohibitory effects. Since upregulation and activity of MMP-2 have been observed in tumors of neuroectodermal origin, and in cancers of the breast, colon, skin, lung, prostate, ovaries, and a host of others, this nanoparticle system can be potentially used for non-invasive diagnosis and treatment of a variety of cancer types.
Veiseh
Omid
O
Department of Materials Science and Engineering, University of Washington Seattle, WA 98195, USA.
Gunn
Jonathan W
JW
Kievit
Forrest M
FM
Sun
Conroy
C
Fang
Chen
C
Lee
Jerry S H
JS
Zhang
Miqin
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D004247:DNA / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry*; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D012604:Scorpion Venoms / Q000737:chemistry*
D000970:Antineoplastic Agents; D010455:Peptides; D034741:RNA, Small Interfering; D012604:Scorpion Venoms; C091539:Chlorotoxin; D004247:DNA; D020778:Matrix Metalloproteinase 2