Nanoparticles Enhanced Hyperthermia - Intracellular Delivery: Fundamentals and Applications - page 590

8.2 Transport Issue and Hyperthermia Dosage

Ability for tissue to achieve the desired temperature largely depends on the transport
mode and the dose of loading nanoparticles.
The typical transport modes for nanoparticles mainly include arterial injection
(Kuznetsov et al. 2001 ), intravenous injection (Yanase et al. 1997 ), direct injection
(Yanase et al. 1998a ) subcutaneous injection (Yanase et al. 1998b ) and so on.
The metabolism of tumor tissue is exuberant, so the vascular system around tumor
is very different from that of normal tissues. The gaps of adjacent endothelial cells
reach 600 ~ 800 nm and tumor impairs lymphatic system. Therefore, the nanopar-
ticles will exudation from the gap and focus on the tumor cells after injection.
In addition, for MNPs, the external magnetic field can be used to control the
movement and determine the position of particles so that to send them to target
cells. Importing from arterial can achieve both artery embolism and hyperthermia,
and intravenous injection is relatively simple but has poor targeting. Direct injection
and subcutaneous injection are only applicable to superficial tumors. Different
injection methods have direct influence on nanoparticle doses for use. For example,
the required doses through direct injections are much smaller than that through
arterial and intravenous injections. In nano hyperthermia, the concentration of load-
ing particles should reach certain value to achieve obvious temperature ascent.
On the other hand, too much nanoparticles can not be injected into human body,
which will delay in the body can subsequently generate some injury. Generally,
the concentration for MNPs is better to be within 5 ~ 10 mg/cm (Pankhurst
et al. 2003 ).
When nanoparticles reach the targeted location, they will integrate with the
tumor cells. Some of them may get into the cells. In other words, the cells swallow
the nanoparticles. The remaining particles will gather on the surface of the cells.
With different structures, some nanoparticles will adhere to the surface separately
whereas some nanoparticles will assemble into agglomerate on the surface of
cells. Different conjunction means with cells contribute differently in generating
heat. For a long time, scientists thought that nanoparticles swallowed by tumor
cells, called intracellular hyperthermia, are the most effective way to kill the
tumor cells. However, some other researchers question this concept. Moroz et al.
( 2002 ) considered that the results of intracellular hyperthermia can not exactly
confirm its very large contribution to the hyperthermia, because there are still some
nanoparticles existing at healthy cells, thus extracellular heat may also contribute
to the results. Rabin (2002 ) questioned that whether intracellular hyperthermia
was superior to extracellular hyperthermia through heat transfer simulation. His
results demonstrated that a single cell uptaking a large amount of nanoparticles can
not reach the hyperthermia temperature. Only when the cells uptake a large number
of nanoparticles together and form a cell cluster with diameter greater than 1 mm
can it reach the effective temperature higher than 41°C. If the nanoparticles num-
bers of intracellular and extracellular are equal, there is no reason to believe
intracellular hyperthermia can achieve better effect, unless intracellular nanoparti-