Biomedical Engineering Reference
In-Depth Information
mainly from the hepatic arterial system, while normal hepatic
parenchyma (NHP) are perfused by the portal venous system.
Administration into the arterial system should then result in
preferential delivery to HCC. Six patients received NanoTherm
injections, while six patients received injections of ferucarbotran
(Resovist, Schering, Berlin, Germany), with a 62 nm hydrody-
namic diameter. In each case, patients received a total of 3.92 mg
of iron, which is a consistent dosage administered intravenously
for MRI diagnostics. Chemotherapy agents included doxorubi-
cin and cisplatin. After nanoparticle injection, the artery was
infused with biodegradable starch microspheres until the tumor
was occluded, to prevent excessive washout. Baseline and follow-
up was conducted with 3.0 T MRI. The MagForce particles dem-
onstrated significantly higher MR signal intensity than Resovist,
and it was speculated that this was due to mechanisms related to
the differences in the particles' coatings. The intratumoral con-
centration of nanoparticles was estimated at 0.032 to 0.01 mg/ml,
and the surrounding NHP were largely clear of nanoparticles.
One patient received a liver transplant 28 days after injection,
and histological analysis was performed on the resected liver.
No nanoparticles were found in the tumor vessels, but numer-
ous macrophages in the interstitial tumor capsule demonstrated
particle uptake. The nanoparticle concentrations achieved in
this study were much too low for hyperthermic treatments, but
some feasibility was demonstrated for arterial embolization
hyperthermia (Moroz et al. 2002).
Although a fairly detailed knowledge base on the mechanisms
behind MFH has been developed, specific areas of basic under-
standing still require some significant development. Magnetic
fluids have been heavily characterized as dispersed solutions but
exhibit significant interactions in biological systems. Theoretical
modeling generally assumes noninteracting particles, but in
vitro and in vivo study have demonstrated that particles will
form aggregates and that this can have significant effects on
magnetic behavior and heating. Current models need to be
modified to factor in these interactions. In addition, although,
thermodynamic scaling arguments suggest that localized, intra-
cellular heating is not occurring, enhanced sensitization and/
or cytotoxic effects have been demonstrated with MFH (Jordan
et al. 1999; Ogden et al. 2009; Creixell et al. 2011; Rodríguez-
Luccioni et al. 2011). The mechanisms behind these enhanced
effects need to be elucidated to fully realize the advantages of
MFH. Another tool that will significantly advance basic under-
standing in the field is noninvasive thermometry. Currently,
minimally invasive probe techniques offer few data points and
introduce unneeded complications to experiments and proce-
dures. Significant development will be required, but compatible
MR, CT, or US thermometry techniques could produce three-
dimensional temperature maps that could be closely matched
with histology and modeling, providing an in-depth knowledge
of
in vivo
heating and treatment efficacy. This level of informa-
tion will be critical in developing the capabilities to provide well-
controlled treatment to complex tumor geometries.
While current iron oxide nanoparticles provide adequate SAR
to produce therapeutic temperatures, there is certainly room
for improvement. Higher magnetic moment nanoparticles are
an area of intense research, including iron-iron-oxide compos-
ites (Zeng et al. 2007), iron-cobalt core structures (Kline et al.
2009), and magnetosomes (Hergt et al. 2005). Improved meth-
ods for synthesizing well-controlled, monodisperse, iron oxide
nanoparticles at the optimal heating radii (refer back to Figure
17. 4) would also significantly increase the SAR achieved. Beyond
the nanoparticle construct, modifying the applied field pro-
vides another means of improving heat generation. Current field
application has been largely limited by unwanted hot spots pro-
duced away from the treatment zone. The field geometry could
be modified to better focus the fields in different regions of the
body (Wust et al. 2006). In addition, optimizing the alternating
wave form (for example, square waves (Morgan and Victora 2010)
or pulsed waves (Foner and Kolm 2009)) could provide higher
power input.
Enhanced nanoparticle delivery is another major area of
development. Uniform nanoparticle distributions confined to
the tumor will provide more complete treatment and better
selectivity in focusing treatment to the tumor. Enhanced deliv-
ery methods could employ biomolecular targeting to preferen-
tially deposit nanoparticles in the tumor region after intravenous
injection (Stelter et al. 2009; Hoopes et al. 2009), but such meth-
ods have yet to demonstrate adequate accumulation for heat-
ing. Magnetic nanoparticles incorporated into multifunctional
platforms may also provide enhanced therapeutic, imaging, and
17.6 What Comes Next?
Decades of research have clearly demonstrated the promise of
magnetic fluid hyperthermia, which is now being realized in
clinical application. However, technology development is a long
and arduous process, and despite years of critical advances, the
field is still in its adolescent phase. Table 17.5 highlights some
of the current technological strengths and areas for potential
improvement. Moving beyond these current limitations is going
to involve continued research in three key areas: furthering basic
understanding, optimizing the heating efficiency, and improv-
ing nanoparticle delivery.
TABLE 17.5
Strengths and Weaknesses of Current Technology
Strengths
Areas for Improvement
• Biocompatibility of iron oxide
nanoparticles
• Demonstrated SAR capable of
therapeutic temperatures
• Uniform fields capable of
penetrating deep tissues, with
minimal adverse effects
• Stable nanoparticle deposits
capable of repeated treatments
over time
• Successful preliminary indications
in combinatorial treatments
• Current capabilities as a
monotherapy
• Heterogeneity of nanoparticle
distributions and treatment
• High nanoparticle
concentrations required for
treatment
• Minimally invasive techniques
required for implantation and
thermometry
• Uncontrolled “hot spots” limit
applied fields
