338
M. Avolio et al.
variation of T 2 as a function of coating thickness on MNPs of two different diameter (5 and 14 nm) and found that SPIOs with 14 nm core and DSPE-mPEG1000
coating provides the highest T 2 relaxivity per-Fe atom among iron oxide nanoparticles reported to date. Also, by means of an in vitro assay mimicking an enzyme-linked
immunosorbent assay (ELISA) they demonstrated that 14 nm SPIOs coated with
DSPE-mPEG1000 and conjugated with specific antibodies can be used for molecular targeting with very high detection sensitivity. Moreover, they proved a great
potential of these SPIOs as MRI CAs for detection of early stage tumors in animal
studies of in vivo tumor imaging. In details, they implanted human U87 glioblastoma cells subcutaneously in nude mice to induce a tumor, that was subsequently
investigated both before and after DSPE-PEG coated SPIOs administration using a
7 T MRI scanner. Results showed a significant enhancement of the contrast in the
tumor region 1 h after the injection of 14 nm SPIOs through the tail vein, confirming
both the high T 2 relaxivity and the targeting capability of these systems.
Although SPIOs in MRI are more suitable to obtain T 2 * relaxation enhancement,
also T 1 -weighted pulse sequences can be executed [57]. However, the contrast effect
is generally appreciable only in the case of the smaller USPIOs, since the required
close interaction between protons and CA can be hampered by the thickness of the
coating on the MNP [58, 59]. In particular, small Manganese ferrite nanoparticles
have been proved to efficiently work as positive contrast agents for MRI by Li et al.
[60], who first reported T 1 -enhanced effects in in vivo MR Images. Despite the
high toxicity of Manganese compounds limits their usage in clinical applications,
2.2 nm superparamagnetic MnFe 2 O 4 nanoparticles resulted to be non-toxic in vitro
and to have such a small r 2 /r 1 ratio to allow their usage as positive MRI CAs. MR
Images of mice livers and kidneys acquired under a 4.7 T magnetic field and using T 1 -
weighted sequences showed high positive contrast after administration of Manganese
ferrite MNPs, in comparison with the pre-contrast images of the control. Indeed, the
longitudinal relaxivity of these particles resulted to be much higher than the typical
r 1 values of molecular Mn agents or Gd-based CAs, being r 1 = 6.61 mM
−1 s
−1 at
4.7 T. Moreover, thanks to the ultra-small size of the particles, which allow long
blood circulation time, MR Images were observed to remain brighter than those of
controls for more than 10 h [60].
The biocompatibility of MNPs for clinical application is controlled by using
appropriate coatings of organic moieties, like sugars or other polymers, which are
attached to the core surface and prevent MNPs elimination by the immune system
of the body. Moreover, the coating can be exploited for multiple and even active
functions: (i) it can be functionalized with antibodies or other molecules which allow
selective targeting of an objective within the body [61]; (ii) drugs can be embedded
within the coating to be specifically sent to malignant cells (i.e., cancer cells) and here
to work as therapeutic agents [47, 48]; (iii) fluorescent molecules can be attached to
the coating, allowing for the MNPs localization within the body thanks to their light
emission.
In vitro and in vivo application of MNPs must face the problem of the particle
toxicity, for which it is primarily necessary to better distinguish among SPIOs and
USPIOs. Their different size is responsible for different fate of these particles inside
M. Avolio et al.
variation of T 2 as a function of coating thickness on MNPs of two different diameter (5 and 14 nm) and found that SPIOs with 14 nm core and DSPE-mPEG1000
coating provides the highest T 2 relaxivity per-Fe atom among iron oxide nanoparticles reported to date. Also, by means of an in vitro assay mimicking an enzyme-linked
immunosorbent assay (ELISA) they demonstrated that 14 nm SPIOs coated with
DSPE-mPEG1000 and conjugated with specific antibodies can be used for molecular targeting with very high detection sensitivity. Moreover, they proved a great
potential of these SPIOs as MRI CAs for detection of early stage tumors in animal
studies of in vivo tumor imaging. In details, they implanted human U87 glioblastoma cells subcutaneously in nude mice to induce a tumor, that was subsequently
investigated both before and after DSPE-PEG coated SPIOs administration using a
7 T MRI scanner. Results showed a significant enhancement of the contrast in the
tumor region 1 h after the injection of 14 nm SPIOs through the tail vein, confirming
both the high T 2 relaxivity and the targeting capability of these systems.
Although SPIOs in MRI are more suitable to obtain T 2 * relaxation enhancement,
also T 1 -weighted pulse sequences can be executed [57]. However, the contrast effect
is generally appreciable only in the case of the smaller USPIOs, since the required
close interaction between protons and CA can be hampered by the thickness of the
coating on the MNP [58, 59]. In particular, small Manganese ferrite nanoparticles
have been proved to efficiently work as positive contrast agents for MRI by Li et al.
[60], who first reported T 1 -enhanced effects in in vivo MR Images. Despite the
high toxicity of Manganese compounds limits their usage in clinical applications,
2.2 nm superparamagnetic MnFe 2 O 4 nanoparticles resulted to be non-toxic in vitro
and to have such a small r 2 /r 1 ratio to allow their usage as positive MRI CAs. MR
Images of mice livers and kidneys acquired under a 4.7 T magnetic field and using T 1 -
weighted sequences showed high positive contrast after administration of Manganese
ferrite MNPs, in comparison with the pre-contrast images of the control. Indeed, the
longitudinal relaxivity of these particles resulted to be much higher than the typical
r 1 values of molecular Mn agents or Gd-based CAs, being r 1 = 6.61 mM
−1 s
−1 at
4.7 T. Moreover, thanks to the ultra-small size of the particles, which allow long
blood circulation time, MR Images were observed to remain brighter than those of
controls for more than 10 h [60].
The biocompatibility of MNPs for clinical application is controlled by using
appropriate coatings of organic moieties, like sugars or other polymers, which are
attached to the core surface and prevent MNPs elimination by the immune system
of the body. Moreover, the coating can be exploited for multiple and even active
functions: (i) it can be functionalized with antibodies or other molecules which allow
selective targeting of an objective within the body [61]; (ii) drugs can be embedded
within the coating to be specifically sent to malignant cells (i.e., cancer cells) and here
to work as therapeutic agents [47, 48]; (iii) fluorescent molecules can be attached to
the coating, allowing for the MNPs localization within the body thanks to their light
emission.
In vitro and in vivo application of MNPs must face the problem of the particle
toxicity, for which it is primarily necessary to better distinguish among SPIOs and
USPIOs. Their different size is responsible for different fate of these particles inside