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Cole A.J.,University of Michigan | David A.E.,University of Michigan | David A.E.,Industrial Science and Technology Network Inc. | Wang J.,University of Michigan | And 5 more authors.
Biomaterials | Year: 2011

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 °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 D20 (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 AUC0-∞. 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. © 2010 Elsevier Ltd. Source


Cole A.J.,University of Michigan | David A.E.,University of Michigan | David A.E.,Industrial Science and Technology Network Inc. | Wang J.,University of Michigan | And 4 more authors.
Biomaterials | Year: 2011

Magnetic iron oxide nanoparticles (MNPs) have been studied to circumvent the limitations of status-quo brain tumor therapy and can be targeted by applying an external magnetic field to lesions. To address the pharmacokinetic shortcomings of MNPs that can limit targeting efficiency, we recently reported a long-circulating polyethylene glycol modified, cross-linked starch MNP (PEG-MNP) suitable for magnetic targeting. Using a rat model, this work explores the biodistribution patterns of PEG-MNPs in organs of elimination (liver, spleen, lung, and kidney) and shows proof-of-concept that enhanced magnetic brain tumor targeting can be achieved due to the relatively long circulation lifetime of the nanoparticles. Reductions in liver (∼12-fold) and spleen (∼2.5-fold) PEG-MNP concentrations at 1. h compared to parent starch-coated MNPs (D) confirm plasma pharmacokinetics observed previously. While liver concentrations of PEG-MNPs remained considerably lower than those observed for D at 1. h through 60 h, spleen values continue to increase and are markedly higher at later time points - a trend also observed with histology. Limited to no distribution of PEG-MNPs was visualized in lung or kidney throughout the 60. h course evaluated. Enhanced, selective magnetic brain tumor targeting (t = 1 h) of PEG-MNPs (12 mg Fe/kg) was confirmed in 9L-glioma tumors, with up to 1.0% injected dose/g tissue nanoparticle delivery achieved - a 15-fold improvement over targeted D (0.07% injected dose/g tissue). MRI and histological analyses visually confirmed enhanced targeting and also suggest a limited contribution of passive mechanisms to tissue retention of nanoparticles. Our results are exciting and justify both further development of PEG-MNP as a drug delivery platform and concurrent optimization of the magnetic brain tumor targeting strategy utilized. © 2011 Elsevier Ltd. Source


Cole A.J.,University of Michigan | Yang V.C.,University of Michigan | Yang V.C.,Tianjin Medical University | David A.E.,University of Michigan | David A.E.,Industrial Science and Technology Network Inc.
Trends in Biotechnology | Year: 2011

Interest in utilizing magnetic nanoparticles (MNP) for biomedical applications has increased considerably over the past two decades. This excitement has been driven in large part by the success of MNPs as contrast agents in magnetic resonance imaging. The recent investigative trend with respect to cancer has continued down a diagnostic path, but has also turned toward concurrent therapy, giving rise to the distinction of MNPs as potential " theranostics" Here we review both the key technical principles of MNPs and ongoing advancement toward a cancer theranostic MNP. Recent progress in diagnostics, hyperthermia treatments, and drug delivery are all considered. We conclude by identifying current barriers to clinical translation of MNPs and offer considerations for their future development. © 2011 Elsevier Ltd. Source


Chertok B.,University of Michigan | Chertok B.,Massachusetts Institute of Technology | Cole A.J.,University of Michigan | David A.E.,University of Michigan | And 3 more authors.
Molecular Pharmaceutics | Year: 2010

Magnetic nanoparticles (MNP) have been widely studied for use in targeted drug delivery. Analysis of MNP biodistribution is essential to evaluating the success of targeting strategies and the potential for off-target toxicity. This work compared the applicability of inductively coupled plasma optical emission spectroscopy (ICP-OES) and electron spin resonance (ESR) spectroscopy in assessing MNP biodistribution. Biodistribution was evaluated in 9L-glioma bearing rats administered with MNP (12-25 mg Fe/kg) under magnetic targeting. Ex vivo analysis of MNP in animal tissues was performed with both ICP-OES and ESR. A cryogenic method was developed to overcome the technical hurdle of loading tissue samples into ESR tubes. Comparison of results from the ICP-OES and ESR measurements revealed two distinct relationships for organs accumulating high or low levels of MNP. In organs with high MNP accumulation such as the liver and spleen, data were strongly correlated (r = 0.97, 0.94 for the liver and spleen, respectively), thus validating the equivalency of the two methods in this high concentration range (>1000 nmol Fe/g tissue). The two sets of measurements, however, differed significantly in organs with lower levels of MNP accumulation such as the brain, kidney, and the tumor. Whereas ESR resolved MNP to 10-55 nmol Fe/g tissue, ICP-OES failed to detect MNP because of masking by endogenous iron. These findings suggest that ESR coupled to cryogenic sample handling is more robust than ICP-OES, attaining better sensitivity in analyses. Such advantages render ESR the method of choice for accurate profiling of MNP biodistribution across tissues with high variability in nanoparticle accumulation. © 2009 American Chemical Society. Source


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Grant
Agency: Department of Energy | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 100.00K | Year: 2000

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