Progress in the characterization of bio-functionalized nanoparticles using NMR methods and their applications as MRI contrast agents
Graphical abstract
Introduction
The interest aroused within the scientific community by nanoparticulate systems has increased during the last few decades, motivated above all by the great potential they have shown in several fields, such as: biomedicine [1], [2], [3], alimentation [4], [5], veterinary science [6], [7], agriculture [8], [9], energy [10], [11], electronics [12], [13], photonics [14], [15], optics [16], [17], sensing [18] and metallurgy [19]. To exploit the potential of nanoparticles in these fields, it is necessary to carry out an exhaustive characterization of these nanosystems. Indeed, the conventional characterization of a nanoparticulate system, consisting of the determination of its morphology, size, polydispersion index and surface ζ-potential, is of fundamental importance. Nevertheless, there are other aspects that are of great importance for specific applications, such as the type and strength of the intermolecular interactions of the materials forming the nanosystem, the residues that are exposed towards their surface, their surface hydro- or lipophilia and the tendency to interact with different compounds, among other aspects.
Nuclear magnetic resonance spectroscopy (NMR) is a multipurpose, high-resolution and non-destructive analytical technique, which can be used for both qualitative and quantitative characterization purposes. The NMR phenomenon was first proposed in 1938 and since then has been steadily studied and developed. Advances in the hardware of spectrometers, including consoles, probes and very stable high magnetic field magnets, have led to great improvements in sensitivity and spectral resolution. Methodological developments in NMR experiments, together with advances in acquisition and processing software have opened the way for NMR studies with larger macromolecules or complexes, also giving access to study the dynamic features of macromolecules [20], [21].
There is a rich variety of well-established mono- and multidimensional liquid and solid NMR experiments, some of which have proven to be very useful for the characterization of different potentially interesting nanosystems. A selection of the most widespread experiments is given in Table 1 [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]. A detailed description of these experiments is beyond the scope of this article and can be found elsewhere [42], [43], [44]. Nevertheless, there is a main division among NMR experiments, separating them into liquid and solid NMR methods. Generally, liquid methods are an attractive possibility because by using them we can elucidate many relevant structural and dynamic properties of nanosystems. However, where liquid NMR acquires a special relevance is in the in vivo applications of these systems, as many in vivo aspects will depend upon their interaction with the water solvent. Nonetheless, a detailed structural and dynamic characterization at the atomic level using this technique is limited by the molecular mass of the studied system, arguably in the order of 40–50 kDa. Beyond this limit, however, it is still possible to obtain certain data of valuable interest, such as small ligand interactions with the nanosystem, average size from diffusion coefficients and acetylation degree.
Taking into account the aforementioned limitations, in very large systems solid NMR experiments can be an excellent alternative or complement, since they are not limited by the size of the molecular system. However, we must take into account that, at the current state of the technique, the amount of information that solid NMR straightforwardly provides may not be as extensive as with liquid NMR.
The applications of NMR cover a wide range of scientific and industrial areas including organic synthesis, structural biology and biomedicine [45], [46], [47]. Among them, the biomedical field is the most prominent, including the drug delivery area. More specifically, NMR can be used for the characterization of the starting materials before the drug delivery system preparation, the understanding of specific structural aspects of the dosage forms, the distribution of the drug through the vehicle or the identification of drug–vehicle interactions, drug–receptor interactions, certain characteristics of a given target or the biodistribution of the drug. All this information in relation to a potential pharmaceutical vehicle is nowadays considered of great importance. Indeed, it will enable or facilitate both the rational design and optimization of the drug vehicle and obtaining a good prediction of its performance at the biological level. This importance can be considered critical for vehicles with specific properties and behavior, such as systems with very peculiar characteristics, mainly derived from their nanoparticulate nature [48], [49], [50]. Finally, it is well known that NMR has allowed us to obtain accurate information that would be impossible to obtain using other analytical techniques [51], [52], [53], [54]. In the following sections, a wide range of NMR applications for the study of nanosystems will be considered, as well as several examples showing the valuable information that can be obtained using this technique. Additionally, the last section is dedicated to magnetic resonance imaging based on nanoparticulate systems.
Section snippets
Nuclear magnetic resonance in nanoparticle characterization
Current NMR methods can provide useful information about the structural composition of nanosystems, as well as the materials used for their preparation, from a qualitative and quantitative point of view. Such information is of particular interest in the case of chemically modified polymers, tailored to achieve specific properties for drug delivery, e.g. by the attachment of certain pendant chemical groups to their surface [23], [26]. NMR experiments also permit the amount of drug effectively
Nuclear magnetic resonance in the characterization of possible in vivo nanoparticle interactions
An important aspect to take into account when we intend to utilize a nanoparticulate system as a biomedical vehicle is its potential tendency to interact with different biological molecules, such as proteins and lipids. Thus, protein adsorption is believed to be the initial event following administration, having a significant impact on the in vivo fate of the system and being decisive in the response of the tissues toward the system, including the appearance of adverse health effects. Proteins
Magnetic resonance imaging (MRI)
The field of molecular imaging has undergone great development over the last decade. The information that is now available from molecular imaging techniques has become of great interest in various biomedical areas, thus attracting numerous research groups. This collection of techniques enables real time visualization, characterization and measurement of biological processes at the molecular and cellular levels [87]. The different molecular imaging modalities include magnetic resonance imaging
Conclusions
NMR and nanotechnology can greatly benefit from one another. In addition to offering interesting tools to characterize the nanoparticles of interest at different stages of their formation (raw materials, bare nanosystem, functionalizated nanosystem), NMR also assists in providing a better understanding as to what happens once the nanoparticles enter the human body. Taking into account that a deeper comprehension of the behavior of nanosystems is needed in order to optimize and/or customize them
Acknowledgements
This work was supported by grants of the UE (Seventh Framework Programme-ERA-NET+-MATERA+, MATERA/BBM-1856 10TMT203011PR), the Ministry of Education and Science (MAT2010-20452-C03-02), MINECO (SAF2011-22771), and Xunta de Galicia (Competitive Reference Groups, Ref.2010/18, FEDER Funds).
Glossary of abbreviations
- CA
- contrast agent
- EDA
- ethylenediamine
- FePt
- iron platinum alloy nanomaterial
- Gd-DTPA
- Gd-diethylenetriaminepentaacetic acid
- Gly-CSA Au MPCs
- glycine–cysteamine gold monolayer protected clusters
- GO
- graphene oxide nanomaterials
- HSA
- human serum albumin
- Lf
- lactoferrin
- MLVs
- multilamellar vesicles
- NPs
- nanoparticles
- PAMAM
- poly(amidoamine)
- PEG
- poly(ethylene glycol)
- PET
- positron emission tomography
- PHOS-PEO
- poly-(4-hydroxystyrene)-block-poly(ethylene oxide)
- SPECT
- single photon emission computed tomography
- SPIO
- superparamagnetic iron
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