Journal
BIOMATERIALS
Volume 32, Issue 8, Pages 2183-2193Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2010.11.040
Keywords
Iron oxide nanoparticles; Magnetic nanoparticles; Magnetic targeting; Polyethylene glycol (PEG); Pharmacokinetics; Reticuloendothelial system (RES)
Funding
- National Institutes of Health (NIH) R01 [CA114612, NS066945]
- Hartwell Foundation
- WCU project of South Korea [R31-2008-000-10103-01]
- NIGMS [GM007767]
- University of Michigan Rackham
- American Foundation for Pharmaceutical Education (AFPE)
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While successful magnetic tumor targeting of iron oxide nanoparticles has been achieved in a number of models, the rapid blood clearance of magnetically suitable particles by the reticuloendothelial system (RES) limits their availability for targeting. This work aimed to develop a long-circulating magnetic iron oxide nanoparticle (MNP) platform capable of sustained tumor exposure via the circulation and, thus, potentially enhanced magnetic tumor targeting. Aminated, cross-linked starch (DN) and aminosilane (A) coated MNPs were successfully modified with 5 kDa (A5, D5) or 20 kDa (A20. D20) polyethylene glycol (PEG) chains using simple N-Hydroxysuccinimide (NHS) chemistry and characterized. Identical PEG-weight analogues between platforms (A5 & D5, A20 & D20) were similar in size (140-190 nm) and relative PEG labeling (1.5% of surface amines - A5/D5, 0.4% - A20/D20), with all PEG MNPs possessing magnetization properties suitable for magnetic targeting. Candidate PEG MNPs were studied in RES simulations in vitro to predict long-circulating character. D5 and D20 performed best showing sustained size stability in cell culture medium at 37 degrees C and 7 (D20) to 10 (D5) fold less uptake in RAW264.7 macrophages when compared to previously targeted, unmodified starch MNPs (D). Observations in vitro were validated in vivo, with D5 (7.29 h) and 020 (11.75 h) showing much longer half-lives than D (0.12 h). Improved plasma stability enhanced tumor MNP exposure 100 (D5) to 150 (D20) fold as measured by plasma AUC(0-infinity). Sustained tumor exposure over 24 h was visually confirmed in a 9L-glioma rat model (12 mg Fe/kg) using magnetic resonance imaging (MRI). Findings indicate that a polyethylene glycol modified, cross-linked starch-coated MNP is a promising platform for enhanced magnetic tumor targeting, warranting further study in tumor models. (C) 2010 Elsevier Ltd. All rights reserved.
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