Biomedical Engineering Reference
In-Depth Information
are encapsulated in nanoparticle delivery vehicles, led to the incorporation of
adjuvant liposomal doxorubicin (Doxil) into the combination therapy.
215,227
Liposome NPs are completely biocompatible with very little toxic or anti-
genic reaction and are biologically inert.
216
While water-soluble drugs can
be trapped in the inner aqueous compartment, hydrophobic compounds may
be located into the liposomal hydrophobic layer thereby protecting the drugs
from the destructive environment in vivo.
216
The disadvantage of liposomal
preparations are their elimination from the systemic circulation by the RES
due to rapid opsonization
228
has been overcome by surface-modification with
flexible hydrophilic polymers such as PEG
228-230
that eliminates plasma
protein absorption on liposome surfaces that causes subsequent recognition
and uptake of liposomes by the RES.
216
The benefits of using liposomes to
encapsulate chemotherapeutic agents include escape from systemic phago-
cytosis resulting in prolonged circulation time, selective agent delivery
through the leaky tumor endothelium (enhanced permeability and retention
effect), as well as reduced toxicity profiles.
229
Thus, the liposome- doxoru-
bicin formulation is widely accepted for clinical practice.
231,232
Subsequent
studies combining RF ablation with adjuvant liposomal doxorubicin dem-
onstrated significant increases in mean tumor coagulation diameter from
combination RF/Doxil therapy (13.1 mm) compared to RF alone (6.7 mm) in
rats.
233
Other animal models also exhibited the same observations in overall
ablation-induced tumor coagulation during confirmatory studies.
215,227,233,234
The results of small and large animal models demonstrated up to 5.6 fold
increase in intratumoral doxorubicin accumulation following RF ablation
with: (1) the greatest amount of intratumoral doxorubicin in the zone imme-
diately peripheral to the central RF area, and (2) smaller amounts of doxoru-
bicin in the central RF-coagulated area suggesting drug deposition in areas
with residual, patent vasculature
235
which explains why liposomal doxoru-
bicin is complementary to RF ablation.
216
Majority of the liposomes were
deposited in an area immediately peripheral to the section coagulated by RF
heating and within the region where non-lethal hyperthermia and increased
destruction is observed.
216,235
Furthermore, the penetration of liposomes
into the coagulation zone is evidence of infiltration of chemotherapy into
the coagulated focus (possibly through residual patent vessels) that may lead
to the completeness of tumor destruction.
216
Finally, improved intratumoral
drug accumulation as well as tumor coagulation led into gains in both animal
survival/tumor growth studies and in preliminary clinical studies.
216
Results of a pilot clinical study where RF ablation (internally cooled elec-
trode) was combined with adjuvant liposomal doxorubicin, 10 patients with
18 intrahepatic tumors were randomized to receive either liposomal doxorubi-
cin (20 mg Doxil) 24 h prior to RF ablation or RF ablation alone (mean tumor
size undergoing ablation was 4.0 ± 1.8 cm).
236
There was no difference in the
amount of tumor destruction between groups immediately following RF but
after 2-4 weeks, patients receiving liposomal doxorubicin had an increase in
