342
M. Avolio et al.
be hardly overcome in the future. These huge SAR values are useful to reduce the
concentration needed to be targeted to the tumor, so limiting possible side effects
after a direct injection of the MNPs suspension and, mainly, they open a new perspective for developing an effective systemic MNP administration by intravenous mode.
Actually, delivery of MNPs to the target tumor by introduction in the blood stream
and in situ accumulation is the main challenge and the most attractive potentiality
of this cancer therapy. Up to now, however, the most effective MFH tests have been
carried out by direct local injection into accessible, massive cancers, typically, subcutaneous tumors induced on mice. As demonstrated by estimates obtained through
simple models [36, 83], indeed, the thermal dose (concentration of mediators multiplied by the SAR value and exposure time) needed to produce a sufficient heat to
successfully eradicate cancer is very high because of the heat losses due to conduction towards surrounding tissue and to blood perfusion. Required thermal dose, and
thus amount of MNPs deposited at the target, increases drastically for small cancer
masses, including metastasis, where dissipative effects are more effective. As an
example, a concentration of 1 mg/cm
3 of the best magnetic mediators mentioned
above [73] is required to increase the temperature of a 3 mm tumor by 5 °C, and
the concentration rapidly increases upon decreasing tumor size (~1/R
2 ). Up to now,
the amount of MNPs delivered by systemic administration, i.e., cellular targeting
or EPR (Enhanced Permeability and Retention) mechanism, seems far from satisfy
these requirements [25].
A further effort of comprehension of the biological processes is also required
to elucidate the killing mechanism induced by the MNP systems activated by an
AFM in the cellular environment at the nanoscale. In many cases, indeed, significant
results in destroying cancer cells have been observed without recording temperature
increase of the culture medium up to hyperthermic range [84]. The hypothesis to
account for this result is that local thermal or mechanical effects induced by the
AFM application can lead to disruption of specific cellular structures. The absence
of a macroscopic temperature increase suggested to rename these phenomena as
‘magnetically mediated energy delivery’ (MagMED) [25], instead of MFH. Investigations of the biological interaction at the nanoscale in order to promote MNP-cell
internalization as well as achieving an effective capability of reaching the target
cancer cell by systemic administration are fundamental to develop new engineered
system to overcome the intrinsic limitations of MFH to treat cancer at the metastatic
stage. The relevance of this task represents one of the most attractive challenge for
the research activity in the field of nanotechnology application in medicine.
14.5 Clinical Applications: State of the Art
and Perspectives
To date, several SPIOs and USPIOs compounds have been approved by Food
and Drug Administration (FDA) for in vivo applications on humans. Feridex
® (or
M. Avolio et al.
be hardly overcome in the future. These huge SAR values are useful to reduce the
concentration needed to be targeted to the tumor, so limiting possible side effects
after a direct injection of the MNPs suspension and, mainly, they open a new perspective for developing an effective systemic MNP administration by intravenous mode.
Actually, delivery of MNPs to the target tumor by introduction in the blood stream
and in situ accumulation is the main challenge and the most attractive potentiality
of this cancer therapy. Up to now, however, the most effective MFH tests have been
carried out by direct local injection into accessible, massive cancers, typically, subcutaneous tumors induced on mice. As demonstrated by estimates obtained through
simple models [36, 83], indeed, the thermal dose (concentration of mediators multiplied by the SAR value and exposure time) needed to produce a sufficient heat to
successfully eradicate cancer is very high because of the heat losses due to conduction towards surrounding tissue and to blood perfusion. Required thermal dose, and
thus amount of MNPs deposited at the target, increases drastically for small cancer
masses, including metastasis, where dissipative effects are more effective. As an
example, a concentration of 1 mg/cm
3 of the best magnetic mediators mentioned
above [73] is required to increase the temperature of a 3 mm tumor by 5 °C, and
the concentration rapidly increases upon decreasing tumor size (~1/R
2 ). Up to now,
the amount of MNPs delivered by systemic administration, i.e., cellular targeting
or EPR (Enhanced Permeability and Retention) mechanism, seems far from satisfy
these requirements [25].
A further effort of comprehension of the biological processes is also required
to elucidate the killing mechanism induced by the MNP systems activated by an
AFM in the cellular environment at the nanoscale. In many cases, indeed, significant
results in destroying cancer cells have been observed without recording temperature
increase of the culture medium up to hyperthermic range [84]. The hypothesis to
account for this result is that local thermal or mechanical effects induced by the
AFM application can lead to disruption of specific cellular structures. The absence
of a macroscopic temperature increase suggested to rename these phenomena as
‘magnetically mediated energy delivery’ (MagMED) [25], instead of MFH. Investigations of the biological interaction at the nanoscale in order to promote MNP-cell
internalization as well as achieving an effective capability of reaching the target
cancer cell by systemic administration are fundamental to develop new engineered
system to overcome the intrinsic limitations of MFH to treat cancer at the metastatic
stage. The relevance of this task represents one of the most attractive challenge for
the research activity in the field of nanotechnology application in medicine.
14.5 Clinical Applications: State of the Art
and Perspectives
To date, several SPIOs and USPIOs compounds have been approved by Food
and Drug Administration (FDA) for in vivo applications on humans. Feridex
® (or