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Nanoparticles
(NPs) are one of the most important tools in the emerging area of nanomedicine.
The behavior of NPs in relevant biological environments, as preclinical setting, may be quite complex due to both their
interactions with biological fluids and the formation of a protein layer,
called protein corona (PC). PC remarkably affects the physicochemical
properties of NPs (size, shape, surface chemistry, aggregation state, etc.) and
consequently their biological fate including their pharmacokinetics,
biodistribution, toxicity and therapeutic efficacy. Strong efforts were applied
to correlate PC composition and observed effect after in vitro/in vivo
experiments, but unfortunately poor reproducibility of data is often assessed.
Biological, chemical and physical properties of NPs along with proteins
composition of PC and features of pathological environments hardly complicate
the study of interactions between PC-NP complexes and their interaction with
target cells. In this contest, in order to
quantitatively and qualitatively evaluate PC adsorbed onto NPs, the optimization of purification/separation
procedures and rigorous and standardized analytical methods become a priority request
to further design tailored nanomaterial able to interact with proteins and
cells in a tunable manner.
Keywords: Nanocarriers,
Molecular size, Nanoparticles, Pharmacokinetics, NP complexes
INTRODUCTION
Nanomedicine is
one of the most active research areas of nanotechnology involving the
application of nanocarriers for the medical prevention, diagnosis, and
treatment of diseases [1]. Polymeric or inorganic nanoparticles (NPs) have the
capacity to incorporate active substances of various characteristics and
protect them from the inhospitable biological environment [2]. Due to their
nanometrical size, NPs show ability to cross tissue barriers and the cell
membrane, thus allowing interaction with the smaller components such as
cellular proteins and other macromolecules [3]. The production of PEG-decorated
NPs could reduce the reticuloendothelial system (RES) uptake, accumulation in
liver, spleen or bone marrow, increasing circulation time and limit
non-specific target uptake ultimately leading to a decrease in toxicity [4].
Further functionalization with targeting ligands, which possess the inherent
ability to facilitate selective binding to cell types, can confer “smart”
properties to NPs [5].
Generally, to
rationally design an efficient nanoparticle-based therapeutic tool able to
selectively transfer drugs to the target site, thus minimizing side effects and
increasing therapeutic compliance, the combination of the nanocarriers
formulative aspects along with a fundamental understanding of the molecular
mechanism involved in regulating nanocarrier-biological interactions is highly
required. In fact, immediately after NPs come into contact with
protein-containing media (such as biological fluids), a layer of proteins,
called the protein corona (PC), is formed on the particle surface. This PC
could remarkably alter the original Np molecular identity affecting their
clearance by RES, cellular uptake, biodistribution and also toxicity.
Furthermore, if the NPs are surface-functionalized with selective ligands, the
absorption of proteins could mask the targeting ability, inhibiting their
biological effects. Thus, it is more than evident that the PC plays a key role
in the interaction of particles with cells after systemic administration [6].
The PC has recently been the subject of
extensive studies aiming to investigate it as complex and multiple layer entity
characterized by proteins that exchange dynamically between the surface and the
surrounding environment (soft corona-SC) and proteins more firmly adsorbed on
the surface of the NPs
(hard corona-HC) [7,8]. An unsolved
As evidence, conflicting reports on
cytotoxicity and biological fates were reported even when similar NPs were
tested [9-12]. For example, Ogawara et al. [13] reported that the PC adsorbed
onto polystyrene NPs prolongs their circulation time, while Nagayama et al.
[14] showed the PC on similar polystyrene NPs is responsible of increased
clearance due to rapid recognition by the scavenger receptors and
internalization by Kupffer cells. Examples of conflicting results can be
found for other biological effects as well (e.g. cytotoxicity, targeting
activity, etc.) [15-18].
Purification and analyses of
PC-NP complexes
To ameliorate
the difficulty interpreting the biological response observed by using NPs,
researchers focalized the attention optimizing the procedure to characterize
the PC around NPs. In particular, evaluating the overall quantity, density,
thickness composition, relative abundance of each protein, protein binding
affinity, and protein conformation. Firstly, PC-NP complexes were separated
from the protein solution. This operation is not simple as the protein-NPs
interaction is regulated by dynamic exchanges and equilibrium that are particularly
sensitive to purification processes, altering the real contribution of the PC
on the NP surface.
Commonly,
sequential cycles of centrifugation/washing represent the most used method,
because it is simple, suitable and gives reliable results [34,35]. However,
multiple purification steps can alter the equilibrium of complexes and may lead
to modification in corona compositions as previously explain [36]. In
particular, purification techniques adopted to isolate and to study the SC,
which is governed by more dynamic exchanges, must be accurately selected and
optimized in terms of operative conditions (time, temperature, stress, etc.).
Moreover, due to high variability, in order to validate the data, several
replicates must be collected and the results must be statistically relevant.
For this
reason, the development of methodologies that minimize the number of
purification steps of the PC-NP complexes in order to lower the possible impact
of the process on their properties is broadly considered as an urgent issue
[37]. Beyond centrifugation, other techniques, summarized in Table 2, have also been applied to
separate and study PC-NP complexes.
These
techniques were successfully applied to isolate PC-NPs complexes in ex-vivo
experiments, namely by incubating NPs in biological medium simulating relevant
biological conditions. In total, only a few experiments reported reproducible
results in terms of identification of PC isolated from plasma after in vivo administration. Actually, the
idea is to exploit NP features and to adapt or combine different methodologies
in function of the type of NPs. As an example, Sakulkhu et al. [45]
demonstrated that the in vitro PC
profile of polyvinyl alcohol-coated SPIONs differs from in vivo ones, after in vivo
administration, by separating the NPs using a strong external magnetic field
and therefore exploiting the unique magnetic properties of the particles. As
another example, a combined approach was proposed by Hadjidemetriou et al. [47]
to recover lipid-based NPs from the blood circulation of rodents after
intravenous administration to investigate the in vivo PC formation as
well as its evolution. In this case size exclusion chromatography followed by
membrane ultrafiltration allowed the isolation of the PC-NP complex and to
recover reproducible samples to identify the PC components.
After
purification, several different approaches were proposed to characterize PC-NP
complex in terms size, thickness, quantity, density, thickness composition,
relative abundance of each protein, protein binding affinity and protein
conformation (Table 3).
The interaction between proteins and the NPs
is another relevant issue that could be addressed by different procedures. As
an example, it is possible to consider physical changes in morphology, size and
zeta potential of the complexes with respect to free NPs as proof of a PC-NP
complex presence. Microscopical analyses using transmission electron microscopy
(TEM) and in some cases, atomic force microscopy (AFM), could allow the
visualization of differences in shape, density, surface and also dimensions of
NPs before and after incubation while dynamic light scattering (DLS) rapidly
identifies changes in dimensional distribution and poly-dispersity.
The interaction in terms of affinity,
association and dissociation constant, and the stability of protein adsorbed
were analyzed by using a plenty of techniques including isothermal titration
calorimetry (ITC), circular dichroism, surface plasmon resonance, quartz crystal
microbalance frequently combined together. Gel filtration has been proposed not
only to separate the protein-NP complexes in incubation media as previously
reported, but also to isolate proteins from the NP surfaces as well as to
provide useful information on kinetic exchange rates for adsorbed proteins [58].
Besides proof of the PC-NPs complex presence,
defining the PC represents a major topic: several researchers reported the use
of electrophoresis as the preferred technology, while protein quantity determination was proposed to
be characterized by mass spectrometry, in which protein samples were digested
into small peptides and simply injected into the analysis instrument [73].
In summary, as
evident, the identification and characterization of the PC cannot be obtained
by a single analytical protocol, but different and complementary technologies
are generally combined. In order to reach the highest level of quality and
standardization in PC identification and characterization, the key point relies
on the choice of the techniques in function of both the type of nanocarriers
and on the analytical parameter to investigate. Using multiple characterization
techniques is therefore crucial to analyze different aspects of the PC (i.e.,
presence of complex, composition of PC, reliability in in vivo conditions, etc.) and to get a better understanding of this
biological entity. Remarkably, some techniques allow to detect the protein
corona in situ (ITC),
while other procedures require the detachment of bound proteins from the
nanocarriers before measurements, thus still representing a controversial issue
on PC analysis, since the adoption of purification methods may change
equilibrium properties of the PC.
CONCLUSION
In recent
years, the advance of nanomedicine as applied science in disease treatments
highlighted a deeper need in understanding the interactions between
nanocarriers and the biological environment aiming to improve their
effectiveness and safety profiles. In this context, the study of the PC
connected to any kind of NP drug carrier and its impact on both biodistribution
and interaction with the target site is of extreme importance. Relevant
information of the PC composition could also be exploited in sample screening
at early research stages. This interest generated a wide number of attempted
experiments, but at a deeper analysis of the results, even if remarkable, the
lack of reproducibility and defined protocols in PC analysis still remain an
urgent issue. In particular, as pointed out in this brief review, those data
often obtained in vitro by simulating
biological environments are affected by a high number of variables and seem not
to be reliable and predictive for in vivo
readouts and therefore their translatability. As also pointed out, numerous
purification and investigation techniques were applied to evaluate and
characterize the PC demonstrating that some technologies could really be useful
in analysing some aspects of PC. Thus, in order to concretely exploit PC-NPs
complexes data, the scientific path in this field will surely pass through an
optimization of the protocols with a rational combination of the different
techniques to finalize a systematic and more reproducible PC study approach.
ACKNOWLEDGEMENT
Supported by MAECI grant (PI Tosi,
Nanomedicine for BBB-crossing in CNS oncologic pathologies) and Emilia Romagna
Region grant (Step-by-step screening: RCUP E56C18002000002).
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