Methotrexate-immobilized poly(ethylene glycol) magnetic nanoparticles for MR imaging and drug delivery.
We report the development of a biostable methotrexate-immobilized iron oxide nanoparticle drug carrier that may potentially be used for real-time monitoring of drug delivery through magnetic resonance imaging. Methotrexate (MTX) was immobilized on the nanoparticle surface via a poly(ethylene glycol) self-assembled monolayer (PEG SAM). The cytotoxicity of the nanoparticle-drug conjugate (NP-PEG-MTX) to target cells was studied with 9L glioma cells. Cellular uptake experiments showed that the uptake of NP-PEG-MTX conjugates by glioma cells was considerably higher than that of control nanoparticles. Magnetic resonance imaging in 9L cells cultured with NP-PEG-MTX of various concentrations showed significant contrast enhancement. NP-PEG-MTX demonstrated higher cytotoxicity in 9L cells to free MTX in vitro. Leucovorin, an MTX antidote, was used to rescue the cells that had been exposed to NP-PEG-MTX or free MTX, and the experiment verified the biocompatibility of NP-PEG-MTX conjugates and the MTX on NP-PEG-MTX conjugates to be the true source of the cytotoxicity to the target cells. TEM results showed that NP-PEG-MTX conjugates were internalized into the 9L cellular cytoplasm and retained its crystal structure therein for up to 144 h, as identified by electron diffraction. This prolonged particle retention may allow physicians to image tumor cells exposed to the NP-PEG-MTX conjugate over an extended therapeutic time course.
Kohler
Nathan
N
Department of Materials Science & Engineering, University of Washington, Seattle, WA98195, USA.
Sun
Conroy
C
Fichtenholtz
Alex
A
Gunn
Jonathan
J
Fang
Chen
C
Zhang
Miqin
M
D000327:Adsorption; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000000981:diagnostic imaging; D045744:Cell Line, Tumor; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000627:therapeutic use; D003287:Contrast Media / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005910:Glioma / Q000000981:diagnostic imaging* / Q000188:drug therapy; D007089:Image Enhancement / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008280:Magnetics / Q000627:therapeutic use; D008727:Methotrexate / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011092:Polyethylene Glycols / Q000737:chemistry*; D011877:Radionuclide Imaging; D051381:Rats
D000970:Antineoplastic Agents; D020099:Coated Materials, Biocompatible; D003287:Contrast Media; D011092:Polyethylene Glycols; D008727:Methotrexate