Abstract
BackgroundCardiovascular diseases are the most prevalent cause of morbidity and mortality affecting millions of people globally. The most effective way to counter cardiovascular complications is early diagnosis and the safest non-invasive diagnostic approach is magnetic resonance imaging (MRI). In this study, superparamagnetic ferrite nanoparticles doped with zinc, exhibiting highly enhanced saturation magnetization and T2 and computed tomography (CT) contrast were synthesized. These nanoparticles have been strategically engineered using bovine lactoferrin (Lf), polyethylene glycol (PEG), and heat shock protein (Hsp)-70 antibody specifically targeting atherosclerosis with potential therapeutic value. The nanocomplexes were further validated in vitro to assess their cytotoxicity, internalization efficiency, effects on cellular proliferation and were assessed for MRI as well as X-ray CT in ex vivo Psammomys obesus rat model.ResultsOptimized zinc doped ferrite nanoparticles (Zn0.4Fe2.6O4) with enhanced value of maximum saturation magnetization value on 108.4 emu/g and an average diameter of 24 ± 2 nm were successfully synthesized. Successfully incorporation with bovine lactoferrin, PEG and Hsp-70 (70 kDa) antibody led to synthesis of spherical nanocomplexes (size 224.8 nm, PDI 0.398). A significantly higher enhancement in T2 (p < 0.05, 1.22-fold) and slightly higher T1 (1.09-fold) and CT (1.08-fold) contrast compared to commercial ferrite nanoparticles was observed. The nanocomplexes exhibited effective cellular internalization within 2 h in both THP-1 and Jurkat cells. MRI scans of contrast agent injected animal revealed significant arterial narrowing and a significantly higher T2 (p < 0.05, 1.71-fold) contrast in adult animals when compared to juvenile and control animals. The excised heart and aorta agar phantoms exhibited weak MRI contrast enhancement in juvenile animal but significant contrast enhancement in adult animal specifically at the aortic arch, descending thoracic aorta and iliac bifurcation region with X-ray CT scan. Histological investigation of the contrast agent injected aorta and heart confirmed site target-specific accumulation at the atherosclerotic aortic arch and descending thoracic aorta of the adult animal with severely damaged intima full of ruptured microatheromas.ConclusionOverall, the study demonstrates the strategic development of nanocomplex based bimodal MRI and CT contrast agents and its validation on Psammomys obesus for atherosclerosis diagnostics.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-016-0157-1) contains supplementary material, which is available to authorized users.
Highlights
Cardiovascular diseases are the most prevalent cause of morbidity and mortality affecting millions of people globally
Zinc doping reduces the chances of iron overloading by crystallographic ferrite iron cation replacement with highly enhanced saturation magnetization of 108.4 emu/g at room temperature, considerably higher than conventional ferrite nanoparticles employed for magnetic resonance imaging (MRI) contrast agent development
Three spherical nanosized complexes based on different combinations of zinc doped ferrite (ZF) nanoparticles, bovine lactoferrin, chitosan and polyethylene glycol (PEG) were developed
Summary
Cardiovascular diseases are the most prevalent cause of morbidity and mortality affecting millions of people globally. Superparamagnetic ferrite nanoparticles doped with zinc, exhibiting highly enhanced saturation magnetization and T2 and computed tomography (CT) contrast were synthesized. These nanoparticles have been strategically engineered using bovine lactoferrin (Lf ), polyethylene glycol (PEG), and heat shock protein (Hsp)-70 antibody targeting atherosclerosis with potential therapeutic value. The most extensively studied class of magnetic nanoparticles for contrast agents development are iron oxide nanoparticles, referred as ferrite nanoparticles This is due to their superparamagnetic nature, biodegradability, inoffensive toxicity profile, low particle dimensions, high surface to volume ratio and reactive surface readily modifiable with biocompatible coatings, targeting/therapeutic molecules as well as other imaging modalities [4, 12,13,14,15]. Zinc is the most suitable candidate as a dopant as Food and Drug Administration (FDA) recommends a high reference daily value (DV) for zinc and iron to be 15 and 18 mg respectively, considerably much more than the values for other possible dopants, for example manganese and cobalt at 2 mg (http://www.fda.gov)
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