Nanotemplate-Engineered Nanoparticles Containing Gadolinium for Magnetic Resonance Imaging of Tumors

Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Investigative Radiology (Impact Factor: 4.44). 03/2008; 43(2):129-40. DOI: 10.1097/RLI.0b013e31815878dd
Source: PubMed


To design nanoparticles containing accessible gadolinium atoms (Gd-NPs) as a contrast agent for magnetic resonance imaging of tumors.
Nanoparticles containing phospholipid-chelates (phosphoethanolamine diethylenetriaminepentaacetate) and DSPE-PEG (MW5000) were prepared from Brij 78 and stearyl alcohol using the nanotemplate engineering approach. After addition of GdCl3, the presence of gadolinium on the surface of nanoparticles was quantified using inductively coupled plasma atomic emission spectroscopy. The in vitro relaxivities of the Gd-NPs in phosphate buffered saline were assessed at 4.7 T. The conditional binding constants of nanoparticle formulations were determined spectrophotometrically by competitive titration. Transmetallation kinetics of Gd from nanoparticles with Cu2+ and Zn2+ as the competing ions was measured in acetate buffer. The biodistribution profiles, pharmacokinetics, and contrast enhancement in tumor region was studied after administration of Gd-NPs to nude mice bearing A549 lung carcinoma xenografts.
Gd-NPs with an average diameter of 138 nm possessing surface chelating functions were prepared from GRAS (generally regarded as safe) materials. The longitudinal relaxivity (r1) and transverse relaxivity (r2) of Gd-NPs in 10% fetal bovine serum at 4.7 T were 7.1 (+/-0.2) and 13.0 (+/-0.7) 1/mM/s, respectively. These pegylated Gd-NPs had enhanced relaxivities and exhibited particle size stability, sufficient binding affinity, and kinetic inertness under physiologic conditions. The contrast enhancement in tumors was demonstrated 40, 120, and 360 minutes after intravenous injection of Gd-NPs at a dose of 0.1 mmol Gd/kg. The Gd plasma concentration of Gd-NPs over a period of 24 hours fit a two-compartmental model with Cl sys = 0.89 mL/h and MRT = 5.93 h. The amount of Gd that accumulated in the tumor region was consistent with the estimated value obtained by T1 measurements using MR imaging.
Pegylated nanoparticles composed of biocompatible, biodegradable materials and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal and accumulated sufficiently in tumors, demonstrating their utility as potential magnetic resonance imaging tumor contrast enhancement agents.

12 Reads
  • Source
    • "NPs less than 50 nm can reach the spleen and marrow through the endothelium of the liver or pass through the lymphatic system. NPs with diameters less than 200 nm can permeate into the tumor microvasculature.19 Thus, the size of NPs should be controlled with respect to the targeted organs. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent studies have shown that bufalin has a good antitumor effect but has high toxicity, poor water solubility, a short half-life, a narrow therapeutic window, and a toxic dose that is close to the therapeutic dose, which all limit its clinical application. This study aimed to determine the targeting efficacy of nanoparticles (NPs) made of methoxy polyethylene glycol (mPEG), polylactic-co-glycolic acid (PLGA), poly-L-lysine (PLL), and cyclic arginine-glycine-aspartic acid (cRGD) loaded with bufalin, ie, bufalin-loaded mPEG-PLGA-PLL-cRGD nanoparticles (BNPs), in SW620 colon cancer-bearing mice. BNPs showed uniform size. The size, shape, zeta potential, drug loading, encapsulation efficiency, and release of these nanoparticles were studied in vitro. The tumor targeting, cellular uptake, and growth-inhibitory effect of BNPs in vivo were tested. BNPs were of uniform size with an average particle size of 164 ± 84 nm and zeta potential of 2.77 mV. The encapsulation efficiency was 81.7% ± 0.89%, and the drug load was 3.92% ± 0.16%. The results of in vitro cytotoxicity studies showed that although the blank NPs were nontoxic, they enhanced the cytotoxicity of bufalin in BNPs. Drug release experiments showed that the release of the drug was prolonged and sustained. The results of confocal laser scanning microscopy indicated that BNPs could effectively bind to human umbilical vein endothelial cells. In the SW620 xenograft mice model, the BNPs could effectively target the tumor in vivo. The BNPs were significantly more effective than other NPs in preventing tumor growth. BNPs had even size distribution, were stable, and had a slow-releasing and tumor-targeting effect. BNPs significantly inhibited colon cancer growth in vitro and in vivo. As a novel drug carrier system, BNPs are a potentially promising targeting treatment for colon cancer.
    Preview · Article · Jul 2012 · International Journal of Nanomedicine
  • [Show abstract] [Hide abstract]
    ABSTRACT: Current advances in magnetic resonance, as a diagnostic modality, are discussed in the context of publications from Investigative Radiology during 2007 and 2008. The articles relating to this topic, published during the past 2 years, are reviewed by anatomic region. The discussion concludes with a consideration of magnetic resonance contrast media, focusing on studies published in the journal, and examining in particular the potential impact of nephrogenic systemic fibrosis.
    No preview · Article · Jan 2009 · Investigative radiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: This article provides a brief overview of recent progress in the synthesis and functionalization of magnetic nanoparticles and their applications in the early detection of malignant tumors by magnetic resonance imaging (MRI). The intrinsic low sensitivity of MRI necessitates the use of large quantities of exogenous contrast agents in many imaging studies. Magnetic nanoparticles have recently emerged as highly efficient MRI contrast agents because these nanometer-scale materials can carry high payloads while maintaining the ability to move through physiological systems. Superparamagnetic ferrite nanoparticles (such as iron oxide) provide excellent negative contrast enhancement. Recent refinement of synthetic methodologies has led to ferrite nanoparticles with narrow size distributions and high crystallinity. Target-specific tumor imaging becomes possible through functionalization of ferrite nanoparticles with targeting agents to allow for site-specific accumulation. Nanoparticulate contrast agents capable of positive contrast enhancement have recently been developed in order to overcome the drawbacks of negative contrast enhancement afforded by ferrite nanoparticles. These newly developed magnetic nanoparticles have the potential to enable physicians to diagnose cancer at the earliest stage possible and thus can have an enormous impact on more effective cancer treatment.
    No preview · Article · Jun 2009
Show more