Biomedical Engineering Reference
In-Depth Information
Hyperthermia
Increases in:
perfusion
permeability
pore size
Increased
pO
2
Traditional
liposomes
ermosensitive
liposomes
Direct
cytotoxic
effects
Synergistic
effects with
chemotherapy
Increased
liposome extravasation
Increased
drug release
inside tumor
Increased
drug delivery to tumor
Increased therapeutic e�cacy
without increasing normal tissue damage
FIGURE 16.1
Summary of beneficial effects of hyperthermia, when combined with liposomal drugs. (Adapted from Kong, G., and Dewhirst,
M. W.
International Journal of Hyperthermia,
15, 5, 1999.)
normal tissue toxicity limits the total amount of drug that
can be delivered. Additionally, even when drug reaches the
site of the tumor, it is extremely difficult to reach all tumor
cells as a result of aberrant properties of tumor vasculature,
which include large intravascular distances and arteriove-
nous shunting (Minchinton and Tannock 2006, Primeau et al.
2005). If it were possible to improve tumor perfusion, then one
could, in principle, deliver drug more effectively to tumors.
It has been shown that hyperthermia can mildly augment
the delivery of free drug to tumors, for example (Kong et al.
2000). Part of the enhancement in delivery could be the result
of heat-mediated increases in perfusion, coupled with the fact
that hyperthermia can augment the cellular uptake of a num-
ber of different drugs and enhance their cytotoxicity by inhib-
iting DNA damage repair mechanisms (Bates and Mackillop
1986). Thermally mediated increases in vascular permeability
could also play a role (Friedl et al. 2003, Umeno et al. 1994),
at least for drugs that are protein bound. Many chemothera-
peutic agents exhibit protein binding (Demant and Sehested
1993, Khan et al. 2008, Li et al. 2007, Ramanathan-Girish and
Boroujerdi 2001, Zemlickis et al. 1994). It has been shown that
heating in the range of 42°C for an hour can increase extrava-
sation of albumin in tumors by 25% over what occurs under
normothermic conditions (Kong et al. 2001). There are many
preclinical reports demonstrating that the combination of
intravenous free drugs with hyperthermia yields improve-
ments in drug delivery and antitumor effects (Herman and
Teicher 1994). A recently reported phase III trial from Europe
showed improvements in local tumor control and progression
free survival in patients with locally advanced soft tissue sar-
comas, randomized to standard of care chemotherapy alone
versus chemotherapy combined with hyperthermia (Issels
et al. 2010). Presumably, the effects discussed here played a
role in the positive effects seen with this trial, the largest ever
conducted in this patient group.
16.4 Effects of Hyperthermia on
Liposome Uptake in tissues
A number of studies have evaluated the effects of hyperther-
mia on liposomal drug accumulation in tumors, at the pre-
clinical and clinical level. Kong and Dewhirst examined these
data extensively in a review paper published in 1999 (Kong and
Dewhirst 1999). Hyperthermia increased liposomal drug accu-
mulation in tumors by factors of 2-8, compared with free drug
plus hyperthermia, depending upon the drug, tumor model, and
temperatures used. One of the challenges in the historical data
was that there were a variety of target temperatures used, as well
as a range of different liposomal formulations and sequences
between timing of liposome administration and treatment
with hyperthermia. Thus it was difficult to conclude the opti-
mal conditions to maximize liposomal drug delivery to tumors
using hyperthermia. To address this issue, Kong systematically
examined a number of parameters that could influence liposome
extravasation, using a single tumor model. He first investigated
the effects of 42°C hyperthermia on liposomal extravasation,
using a range of different-sized liposomes (Kong et al. 2000). The
largest thermally mediated enhancement in liposomal extravasa-
tion occurred with 100 nm liposomes. Augmentation of extrava-
sation was also seen with 200 and 400 nm liposomes, but not to
the same extent. Thermal dependence of extravasation was spe-
cific for tumor tissue, as hyperthermia did not appear to enhance
liposomal extravasation in normal tissues. These results clearly
showed that hyperthermia was not increasing liposomal extrav-
asation in tumor microvessels by increasing general permeabil-
ity. Alternatively, it appeared to be capable of opening pores in
the vascular endothelial lining of tumor microvessels that were
large enough to enhance 100 nm-400 nm liposomal drug deliv-
ery (Figure 16.2a). Kong went on to examine the temperature
dependence of liposomal extravasation, finding a threshold for
