1 3
Topics in Current Chemistry (2020) 378:40
chemical exchange saturation transfer (CEST) or hyperpolarization, most MRI CAs
produce contrast by altering the relaxation times of the surrounding water protons
[254, 255]. The capacity of a CA to decrease the relaxation times (T 1 or T 2 ) is given
by a parameter known as relaxivity (r 1 or r 2 ), which is expressed in mM
−1
·s
−1
.
In MRI, among the most commonly used CA are chelates of paramagnetic
gadolinium(III) ions (Gd
3+
). However, conventional Gd-chelates have some important limitations, such as the lack of diagnostic specificity and the toxicity associated
with their use as a result of the unexpected release of free Gd ions [256, 257]. Magnetic NPs have emerged as a promising alternative to overcome these limitations
[258].
4.1 IONPs in Tumor Diagnosis
4.1.1 Untargeted IONPs
The evaluation of IONPs as CAs in cancer research is performed mainly in rodent
models, called ‘indirect xenografts’ [259]. Cancer cells can be implanted either
into a tissue unrelated to the original tumor site (heterotopic model) or into the
corresponding anatomical position (orthotopic model) [260] (Fig. 7). The route of
administration of magnetic NPs is also relevant as it influences the biodistribution
and pharmacokinetics of the CA. Several administration routes have been used in
preclinical studies, mainly intratumoral, intraperitoneal or intravenous injection;
for obvious reasons, the latter is the most interesting for clinical applications. After
intravenous administration, IONPs have been described to accumulate in tumors
due to the EPR (Enhanced Permeability and Retention) effect. This passive transport is determined by the high vascularization of tumors, and therefore increased
blood flow, together with increased vascular permeability and poor lymphatic drainage [261]. Efremova et al. [262] developed IONPs for diagnosis of breast cancer in
a heterotopic model. They observed that IONPs accumulated passively inside the
tumor 24 h after intravenous injection using T 2 -weighted MR images. Similar studies have been conducted using orthotopic models of breast cancer [263, 264], pancreatic cancer [265] and glioblastoma multiforme (GBM) [266]. All these studies
conclude that IONPs accumulated in the tumor due to the EPR effect; however, most
of them lack quantitative analyses, which are necessary to determine the amount of
IONPs that actually reach the tumor.
Intratumoral administration could be an alternative for tumor therapy when the
CA is not able to reach the tumor by a venous route. However, this approach has
serious limitations for diagnostic applications since, in most cases, it would not add
any useful information to that already provided by the MR images without CA. Furthermore, intratumoral administration makes no sense when it comes to very early
diagnosis, detection of metastasis or in the case of inaccessible tumors. Nevertheless, several preclinical studies have been conducted using intratumoral injection
of IONPs [267–269]. The authors used qualitative MRI to evaluate the distribution of IONPs throughout the tumor, which showed that IONPs spread slowly and
inefficiently. Therefore, in these studies the information provided by MRI after the
69
Reprinted from the journal
Topics in Current Chemistry (2020) 378:40
chemical exchange saturation transfer (CEST) or hyperpolarization, most MRI CAs
produce contrast by altering the relaxation times of the surrounding water protons
[254, 255]. The capacity of a CA to decrease the relaxation times (T 1 or T 2 ) is given
by a parameter known as relaxivity (r 1 or r 2 ), which is expressed in mM
−1
·s
−1
.
In MRI, among the most commonly used CA are chelates of paramagnetic
gadolinium(III) ions (Gd
3+
). However, conventional Gd-chelates have some important limitations, such as the lack of diagnostic specificity and the toxicity associated
with their use as a result of the unexpected release of free Gd ions [256, 257]. Magnetic NPs have emerged as a promising alternative to overcome these limitations
[258].
4.1 IONPs in Tumor Diagnosis
4.1.1 Untargeted IONPs
The evaluation of IONPs as CAs in cancer research is performed mainly in rodent
models, called ‘indirect xenografts’ [259]. Cancer cells can be implanted either
into a tissue unrelated to the original tumor site (heterotopic model) or into the
corresponding anatomical position (orthotopic model) [260] (Fig. 7). The route of
administration of magnetic NPs is also relevant as it influences the biodistribution
and pharmacokinetics of the CA. Several administration routes have been used in
preclinical studies, mainly intratumoral, intraperitoneal or intravenous injection;
for obvious reasons, the latter is the most interesting for clinical applications. After
intravenous administration, IONPs have been described to accumulate in tumors
due to the EPR (Enhanced Permeability and Retention) effect. This passive transport is determined by the high vascularization of tumors, and therefore increased
blood flow, together with increased vascular permeability and poor lymphatic drainage [261]. Efremova et al. [262] developed IONPs for diagnosis of breast cancer in
a heterotopic model. They observed that IONPs accumulated passively inside the
tumor 24 h after intravenous injection using T 2 -weighted MR images. Similar studies have been conducted using orthotopic models of breast cancer [263, 264], pancreatic cancer [265] and glioblastoma multiforme (GBM) [266]. All these studies
conclude that IONPs accumulated in the tumor due to the EPR effect; however, most
of them lack quantitative analyses, which are necessary to determine the amount of
IONPs that actually reach the tumor.
Intratumoral administration could be an alternative for tumor therapy when the
CA is not able to reach the tumor by a venous route. However, this approach has
serious limitations for diagnostic applications since, in most cases, it would not add
any useful information to that already provided by the MR images without CA. Furthermore, intratumoral administration makes no sense when it comes to very early
diagnosis, detection of metastasis or in the case of inaccessible tumors. Nevertheless, several preclinical studies have been conducted using intratumoral injection
of IONPs [267–269]. The authors used qualitative MRI to evaluate the distribution of IONPs throughout the tumor, which showed that IONPs spread slowly and
inefficiently. Therefore, in these studies the information provided by MRI after the
69
Reprinted from the journal