Biomedical Engineering Reference
In-Depth Information
(a)
120
(b)
100
Cluster 1
Cluster 2
80
60
40
Cluster 1
Cluster 2
Centroid
20
0
0
10
20
30
40
50
60
0
10
20
30
40
50
60
Hb saturation (%)
Time (days)
(c)
(d)
70
35
60
30
Cluster 1
Cluster 2
50
40
30
20
25
20
15
Cluster 1
Cluster 2
10
10
0
5
0
50
100
150
0
10
20
30
40
Post-trt total Hb (µM)
Pre-trt Hb saturation (%)
FIGURE 16.4
Effects of doxorubicin concentration, perfusion, and oxygenation on antitumor effect of LTSL-Dox + hyperthermia. (a) Results of
a k-means cluster analysis of hemoglobin saturation and total hemoglobin, measured at baseline for individual animals bearing SKOV3 ovarian
carcinoma xenografts that were treated with LTSL-Dox or free doxorubicin ± hyperthermia. Two clusters were identified when comparing total Hb
vs. Hb saturation, prior to treatment. Cluster 1 had relatively low Hb saturation and low hemoglobin concentration, compared with cluster 2. The
time to reach 3 ×
treatment volume was significantly shorter for cluster 1, which tended to be more hypoxic and have lower blood volume, com-
pared with cluster 2 (
p
= 0.003; b). (c) and (d) show highly significant correlations between pretreatment Hb saturation and time to 3 × pretreatment
volume, and the posttreatment total Hb and doxorubicin concentration (
r
= 0.8,
p
= 0.01, and
r
= 0.89,
p
= 0.001, respectively, by Spearman rank
correlation). These data show that even for LTSL-Dox with hyperthermia, individual variations in the amount of drug delivered and the oxygen-
ation state have a strong influence on growth delay time. (Palmer, G. et al.,
J Control Release
, 142, 2010. With permission.)
The effects of hyperthermia on nanoparticle extravasation
from tumor microvessels and on thermosensitive liposome con-
tent release are summarized in Figure 16.4. Under normother-
mic conditions, a few liposomes extravasate via the EPR effect to
heterogeneously collect in perivascular regions. Hyperthermia
at 40-42°C increases pore sizes between endothelial cells, per-
mitting greatly enhanced extravasation of liposomes into the
interstitial space. Thermosensitive liposomes rapidly release
their contents upon reaching their transition temperature,
which bathes the heated zone in free drug, which can diffuse
down its concentration gradient to reach tumor cells.
Kong and Needham were the first to directly compare the antitu-
mor efficacy of hyperthermia combined with LTSL loaded with
doxorubicin (LTSL-Dox) to that of a Doxil
•
-type formulation
and free doxorubicin (Kong et al. 2000, Needham et al. 2000).
Using the FaDu human squamous cell carcinoma line, they were
able to show that hyperthermia + LTSL-Dox yielded 25x and 4x
higher drug concentrations in tumor, compared with hyperther-
mia combined with free drug or the Doxil
•
-type formulation,
respectively. This increase in drug concentration was correlated
with enhanced antitumor effect, yielding long-term tumor con-
trol in several subjects in replicate experiments, whereas free
doxorubicin exhibited virtually no antitumor effect. They fur-
ther showed that the amount of doxorubicin bound to DNA was
higher in the LTSL-Dox plus hyperthermia group than other
groups (Kong et al. 2000). Since DNA is one of the putative tar-
gets of doxorubicin, this result was consistent with the improved
antitumor effect seen with this drug. These results strongly sug-
gest that the increase in drug concentration achieved with LTSL-
Dox with hyperthermia is key to its improved antitumor effect.
In a recent report, Palmer et al. showed that the extent of
growth delay achieved in SKOV3 ovarian carcinoma xenografts
following LTSL-Dox + hyperthermia was related to doxorubicin
16.6 Factors that Influence
Effectiveness of LtSL-Dox When
Combined with Hyperthermia
16.6.1 Drug Delivery and Oxygenation
The primary drug that has been studied with this formulation
is doxorubicin, because it is easily loaded into liposomes, using
a pH gradient loading method (Needham and Dewhirst 2001).
