Biomedical Engineering Reference
In-Depth Information
16
Using Hyperthermia to
Augment Drug Delivery
16.1 Introduction ............................................................................................................................ 279
16.2 Mild Hyperthermia Is Ideal for Augmenting Drug Delivery and
Efficacy in Tumors .............................................................................................................279
16.3 Fundamental Limitations for Effective Drug Delivery and Antitumor Activity ......... 279
16.4 Effects of Hyperthermia on Liposome Uptake in Tissues ................................................ 280
16.5 Development of Thermally Sensitive Liposomes ............................................................... 282
16.6 Factors That Influence Effectiveness of LTSL-Dox When Combined
with Hyperthermia ................................................................................................................. 283
Drug Delivery and Oxygenation • Vascular Targeting and HIF-1
16.7 Use of Imaging to Quantify Drug Delivery from LTSL-Dox and Establishment
of Treatment Optimization Strategies ................................................................................. 285
16.8 Clinical Applications of LTSL-Dox ...................................................................................... 286
Canine Trial • Human Trials • Primary Hepatocellular Carcinoma • Chest Wall
Recurrences of Breast Cancer
16.9 Future Directions .................................................................................................................... 288
Additional Applications for LTSL-Dox
References ............................................................................................................................................ 289
Mark W. Dewhirst
Duke University Medical Center
16.1 Introduction
Song 1984). The efficacy of many drugs is limited by hypoxia, so
any treatment that improves tumor oxygenation is also likely to
improve the efficacy of chemotherapy (Brown and Wilson 2004).
When temperatures are elevated further, however, hyperthermia
can cause vascular damage, which would impede drug delivery
(Song et al. 2001). There are circumstances where thermal abla-
tive therapy has been combined with liposomal drugs, which
will be discussed later in more detail. However, even in this situ-
ation, the addition of liposomal drugs is designed to take advan-
tage of vascular changes at the edge of the ablation zone, which
again is in the mild hyperthermia temperature range (Ahmed
and Goldberg 2004, Mostafa et al. 2008, Poon and Borys 2009).
This chapter will provide an overview of the use of hyperthermia
to augment drug delivery and antitumor effects of drug-carrying
liposomes. The focus of this chapter will be on applications as
opposed to design of liposomal formulations. Interested readers
are encouraged to seek out several in-depth reviews on nuances of
liposome formulations that have been published previously (Kong
and Dewhirst 1999, Koning et al. 2010, Landon et al. 2011, Lindner
and Hossann 2010, Lindner et al. 2005, Tashjian et al. 2008).
16.2 Mild Hyperthermia Is Ideal
for augmenting Drug Delivery
and Efficacy in tumors
16.3 Fundamental Limitations
for Effective Drug Delivery
and antitumor activity
We will focus on the effects of hyperthermia treatment in the
temperature range of 39-42°C, because it is in this tempera-
ture range that profound physiologic effects occur in tumors
that can mediate improvements in drug delivery (Song et al.
2001) (Figure 16.1). There are literally dozens of reports show-
ing that temperatures in this range increase tumor perfusion,
oxygenation, and vascular permeability (Dewhirst et al. 2005,
One of the basic limitations of traditional drug delivery fol-
lowing intravenous free drug administration is that drugs do
not reach the target volume in sufficient quantities to be effi-
cacious. Part of the limitation is due to the fact that there is
indiscriminate distribution throughout the body. As a result,
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