Journal of Nanomaterials & Molecular NanotechnologyISSN: 2324-8777

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Commentary, J Nanomater Mol Nanotechnol Vol: 4 Issue: 3

Zinc Ferrite Nanoparticles as Highly Effective Magnetic Resonance Imaging Contrast Agents with Emphasis on Atherosclerosis

Rajneesh Chaudhary, Rupinder K Kanwar and Jagat R Kanwar*
Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research(NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR)Strategic Research Centre, Faculty of Health, Deakin University, Geelong,Pigdons Road, Waurn Ponds, Geelong, Victoria, Victoria 3217, Australia
Corresponding author : Professor Jagat Rakesh Kanwar
Nanomedicine- Laboratory of Immunology and Molecular Biomedical Research (NLIMBR), School of Medicine (SoM), Molecular and Medical Research (MMR) Strategic Research Centre, Faculty of Health, Deakin University, Geelong, Pigdons Road, Waurn Ponds, Geelong, Victoria, Victoria 3217, Australia
Tel: 0061 3 52271148; Fax: 0061 3 52272539
E-mail: [email protected]
Received: May 03, 2015 Accepted: June 12, 2015 Published: June 16, 2015
Citation: Chaudhary R, Kanwar RK, Kanwar JR (2015) Zinc Ferrite Nanoparticles as Highly Effective Magnetic Resonance Imaging Contrast Agents with Emphasis on Atherosclerosis. J Nanomater Mol Nanotechnol 4:3. doi:10.4172/2324-8777.1000164


Zinc Ferrite Nanoparticles as Highly Effective Magnetic Resonance Imaging Contrast Agents with Emphasis on Atherosclerosis

Conventionally and most commonly used commercial contrastagents for magnetic resonance imaging (MRI) diagnostics are based on paramagnetic gadolinium Gd (III) chelates. They have widespread use in cancer and cardiovascular imaging where they are perfused directly into the blood vessel followed by MRI of the diseased tissues. The functional mechanism of electron dense gadolinium complex is by interaction with the surrounding protons and shortening the T1 relaxation time.

Keywords: Cardiovascular imaging; MRI; Gadolinium

Conventionally and most commonly used commercial contrast agents for magnetic resonance imaging (MRI) diagnostics are based on paramagnetic gadolinium Gd (III) chelates. They have widespread use in cancer and cardiovascular imaging where they are perfused directly into the blood vessel followed by MRI of the diseased tissues. The functional mechanism of electron dense gadolinium complex is by interaction with the surrounding protons and shortening the T1 relaxation time [1]. Commercially available gadolinium based MRI contrast agents include Magnevist® (Bayer Healthcare), Omniscan® (GE Healthcare Inc.), Dotarem® (Guerbet), Prohance® (Bracco Diagnostic Inc.), etc. Although the gadolinium based commercial contrast agents have been approved by the Food and Drug Administration (FDA) in the United States of America, their use is strictly regulated due to several toxicity issues. Gadolinium is highly toxic in vivo and therefore must be modified with organic chelators such as diethylene triamine pentaacetic acid (Gd-DTPA) or 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid (Gd-DOTA) and their modified complexes [2]. Paramagnetic electron dense chelated gadolinium complex enhances relaxivity primarily by direct inner gadolinium cation dipolar interaction with surrounding water protons and feebly by outer hydrogen bonding interactions between water molecules. The cross-linked chelating organic compound is chosen in such a way that it renders the complex thermodynamically stable, maximises water molecule interaction, shortens optimal water residence time and slows tumbling rate (depends on molecular weight of the ligand). All these factors may improve the relaxation efficiency of gadolinium based contrast agents but toxicity is still a major issue concern. Even after chelation with amino polycarboxylic acids, gadolinium based contrast agents such as Gd-DTPA complexes have been shown to lead to nephrogenic systemic fibrosis (NSF) [3] and nephrogenic fibrosing dermopathy (NFD) [4] in patients with renal insufficiency which may even lead to fatality. The exact mechanism of NSF is still not yet fully understood. Main reason cited for gadolinium chelate toxicity is transmettalation by divalent or trivalent cations of iron, zinc, copper or calcium in which the cation competes with gadolinium for site in the complex releasing toxic gadolinium (III) cations [4,5].
Since the application of dextran coated magnetite nanoparticle complex as effective water T2 relaxation time shortening agent by Ogushi et al,Superparamagnetic iron oxide nanoparticles (SPIONS) or Ferrite nanoparticlesbased contrast agentshave been employed inmagnetic resonance imaging diagnostic technology.Iron oxide nanoparticle complexes based MRI contrast agents have been widely employed for diagnosis of cardiovascular diseases and various forms of cancer. Engineered ferrite nanoparticle based contrast agents are providing an increased contribution in the field of MRI diagnostic and molecular imaging by providing several advantages over traditional gadolinium based contrast agents. Toxicity is considerably reduced due to biodegradability and detectability is greatly improved as they contain a high payload of contrast generating material and therapeutic agents. These attributes are further improved with the additional site-specific molecular targeting, hyperthermia, drug delivery therapeutic applications. Furthermore, zinc can be doped for maximizing saturation magnetization (MS) as the Food and Drug Administration (FDA) recommends a higher reference daily value (DV) for micronutrients zinc and iron to be 15 and 18mg respectively, considerably a lot more than the DV for manganese and cobalt at 2 mg ( The empirical parameter affecting the T2 relaxivity of the ferrite nanoparticle based MRI contrastagents is dictated by the value of saturation magnetization (MS). Higher MS value of leads to an increased T2 relaxation of the surrounding protons.Superparamagnetic ferrite nanoparticles as contrast agent align with the external magnetic field and induce strong localized magnetizations within tissues by interaction with surrounding water protons. The mode of action of ferrite nanoparticles is by enhancing the relaxation rate or shortening the T2 relaxation time by increasing field inhomogeneity of surrounding protons to creating strong negative MRI contrast. The strong interaction of individual superparamagnetic nanoparticles with the free protons at their spatial locations induces a strong de-phasing effect leading to significant shortening of T2 relaxation time. The negative contrast enhancement of the nanoparticles is directly proportional to the magnetic moments of the nanoparticles. The dipolar outer sphere interaction mechanism of the nanoparticle with the surrounding water protons magnetic moments has been theoretically defined as [6]:
R2 = 1/T2 = (a / dNPD) γ2 μ2 CNP J (ω, τD)
Nanoparticle size, magnetic moment and concentration have an inverse relationship with relaxation rate and represented as dNP, μ and CNP respectively. Gyromagnetic potential is represented as γ, spectral density function as J (ω, τD) and ‘a’ is a constant. Therefore for effective contrast enhancement, right balance of size and magnetic moment of the nanoparticle is the primary prerequisite for ferrite nanoparticle based contrast agent development. The ferrite nanoparticles should have size optimally small enough to have maximised magnetization and large enough without compromising magnetization or losing superparamagnetivity. Complete superparamagnetic behaviour of nanoparticles ensures agglomeration is avoided due to absence of remanent magnetization (Mr). In addition as the T2 negative contrast enhancers, ferrite nanoparticles may also act as T1 contrast enhancers after nanoparticle cellular breakdown in vivo as Fe(III) which is a strongly paramagnetic.
Doping of transition metals such as cobalt, zinc, nickel, copper with the ferrite core has a substantial impact on its magnetic properties [7]. Enhanced saturation magnetization (MS) of various combinations of dopants within the nanoparticulate ferrite spinal structure has been widely reported. In vivo toxicity of zinc doped ferrite nanoparticle based contrast agents can be minimised playing a huge advantage over conventional gadolinium based contrast agents where toxicity is a major issue. Additionally, the nanoparticles are biodegradable in vivo releasing zinc and iron as micronutrients. Clinically approved iron oxide nanoparticles based contrast agents include Ferridex® and Resovist® (Bayer Schering Pharma AG).
Iron homeostatis has a prime significance for the body to keep balanced tissue iron levels and may be defined as a balance between amount of iron ingested and metabolised. Haemochromatosis, genetic or acquired is a symptom of excess iron in the body, deficiency of iron leads to anaemia. Different approaches have been employed to observe iron content within the body. A direct correlation can be associated with increased serum ferritin levels and depletion of iron stores, decreased ferritin receptor and mild iron deficiency, decreased haemoglobin and overt anaemia [8]. Serum ferritin level less than 10ng/ml have been associated with low transferrin saturation and iron-deficient erythropoiesis as observed with iron deficient anaemia patients (n=21) with low serum iron level of 20.4 ± 1.7 μg/100 ml [9]. Serum iron level for normal men (n=75) and women (n=44) was found to be 123 ± 4.8 μg/100 ml and 94.9 ± 5.8 μg/100 ml respectively. Serum ferritin level was observed to be of 69ng/ml for normal men and 35 ng/ml for normal women, proportionate with serum iron level. Primary haemochromatosis patients (n=8) and refractory patients (n=13) had excessive serum iron concentration of 246.5 ± 23.1 mg/100 ml and 171.8 ± 16.8 mg/100 ml respectively. The upper limit of serum ferritin levels could not be well defined due to skew distribution however none of the normal men and women had a serum ferritin level of over 200 ng/ml.
A study conducted to improve the understanding of the borderline value of subclinical iron deficiency. The dynamics of serum ferritin, serum transferrin receptor (sTfR) and transferrin to log ferritin ratio (TfR-F) were observed on 65 healthy non anaemic individuals (22 men and 42 women) [10]. The study concluded the limit irondeficient erythropoiesis that serum ferritin to be 22 μg/L, and sTfR to be 2.43 mg/L. The TfR-F value of 1.81 was found to be more reliable and decisive for detecting subclinical iron deficiency, especially when the ferritin and sTfR values are ambiguous. Haemoglobin levels on the other hand showed rapid depletion only in the later stages of iron deficiency.
The effect of iron overload on atherosclerosis progression is still debatable. Studies have indicated that iron overload may promote the modification of low density lipoproteins (LDL) to its highly oxidised form, triggering atherogenesis [11-13] and it was hypothesised that increased iron levels are pro-atherogenic. A study was conducted to specifically observe this effect of iron overloading on atherosclerosis with apoE mice [14]. The control mice were fed 0.02% iron diet and the subject mice were fed 2% iron diet for 24 weeks (n=5 per group). Iron overloading was assessed by ferritin levels in the aorta, liver and serum, iron fed mice showed multiple fold increase compared to control. The iron overloaded mice lesions showed over fifty percent reduction in plaque sizes as compared to control mice at all stages of atherosclerosis progression. Histological analysis revealed the presence of large amounts of iron present in the aorta tissues clearly indicating that iron does not act as LDL oxidiser within the arterial wall. The exact mechanism behind this anti-atherogenic effect of iron overloading is still unclear.
Zinc has been directly correlated with improved cell mediated immunity against cancer with tumor bearing mice [15]. The normal serum zinc level (SZL) was found to be 90.2 ± 5.1 μg/dl and 89.1 ± 5.6 μg/dl with 8 week-old male strain A/RB (n=30) and C3H female mice (n=10) respectively. Mice serum zinc levels were substantially reduced post tumor-induction with fibro-sarcoma and by transplantation of sarcoma-180 (S-180), Earlich’s Ascites Carcinoma (EAC), and Dalton’s Lymphoma (DL) observed at 7, 10 and 17 days. Tumor volumes were significantly reduced post-chemotherapeutic treatment performed with 5-FU and Mitomycin C, inversely proportionate with the serum zinc level and directly proportionate with the serum copper concentration (SCL). Zinc supplementation was shown to have a direct correlation splenocyte proliferation of tumor bearing mice in vitro comparable to that of ConA stimulated spleen (1 μg/ ml). The study indicated that zinc could have a major role in tumor suppression and immune stimulation.
Zinc plays an important role in maintaining proper HDL to LDL ratio, thus playing an important role in cardiovascular health. Effect of zinc supplementation on atherosclerosis was studied with New Zealand white rabbits [16]. Three groups of New Zealand rabbits (n=6) with 2.5 kg mean weight were fed normal, high cholesterol diet (HCD) and high cholesterol diet supplemented with zinc (HCD-Zn) (zinc carbonate, 1 g/kg body weight). Blood samples analysis after eight weeks of treatment revealed reduced levels of cholesterol, triglyceride, HDL and LDL with HCD-Zn fed group as compared to HCD fed group. On the other hand, higher number of RBCs, platelets and hemoglobin were also observed with HCD-Zn fed group, similar number of leukocytes were observed. The average lesion area analysis with the aortic arch cut into three specific segments [17] revealed over three times less atherosclerotic lesion area for HCD-Zn fed group as compared to HCD fed group. In the following study by the same group, three groups of rabbits with similar mean weight diet were fed normal diet (n=6), high cholesterol diet 1% w/w (n=5) and high cholesterol 1% w/w with zinc loading 1g/ kg body weight (n=5) for 8 weeks [18]. Zinc levels in normal diet-fed and high cholesterol fed mice were kept normal at 50 and 60 mg/kg respectively. Significantly lower cholesterol plasma levels and more than 50% reduction in aortae tissue cholesterol levels were observed with high cholesterol-zinc supplemented rabbits as compared to high cholesterol fed diet rabbits. The cholesterol oxidation products (7-b OH-cholesterol, 5,6-b cholesterol epoxide, 5,6-a cholesterol epoxide, 7-keto cholesterol) assessed for whole aortae segments also showed significant reduction with high cholesterol-zinc supplemented rabbits as compared high cholesterol diet fed rabbits. This clearly indicates that Zinc supplementation is anti-atherosclerotic and prevents lipid peroxidation within the arterial wall.
Significantly decreased zinc concentration and increased activity of zinc based enzymes, malic and lactic dehydrogenase in human serum is closely related to myocardial infarction [19]. Mean serum zinc concentration below 82 μg per 100 ml is clearly linked to instances of myocardial infarction on a study conducted with eight observations on eight acute myocardial infarction patients with 99% significance. Significant and uniform increase in the activity of lactic dehydrogenase was observed post myocardial infarction, malic dehydrogenase also showed similar pattern. The activity levels were back to normal in seven to eleven days. The serum lactic dehydrogenase activity is a crucial diagnostic tool for myocardial infarction. Zinc is indispensable for activating lactic dehydrogenase but excess of the zinc ions will lead to decrease in the enzyme activity [20]. Zinc could be effective in preventing myocardial infarction by inhibiting the activity of lactate dehydrogenase when used as diagnostic contrast agent.
Numerous modified iron oxide nanoparticle based contrast agents have been developed worldwide targeting atherosclerosis for MRI diagnostics [21,22] and doping the nanoparticle spinel crystal core with zinc would have critical benefits.


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