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Experimental Therapeutics |
Departments of Biomedical Engineering [G. K.] and Mechanical Engineering and Material Science [G. A., D. N.], Duke University, Durham, North Carolina 27708, and Departments of Medicine [W. P. P., O. M. C.] and Radiation Oncology [R. D. B., M. W. D.], Duke University Medical Center, Durham, North Carolina 27710
The
tumor drug concentrations, drug distributions, and therapeutic
efficacies achieved by three fundamentally different liposomes,
nonthermosensitive liposome (NTSL), traditional thermosensitive
liposome (TTSL), and low temperature sensitive liposome (LTSL); free
doxorubicin (DOX); and saline in combination with hyperthermia (HT)
were directly compared in a human tumor xenograft model. NTSL is a
nonthermosensitive liposome in the physiological temperature range,
TTSL is a traditional thermosensitive liposome that triggers in the
range of 
42–45°C and releases drug over 30 min, and LTSL is a
new low temperature sensitive liposome that triggers in the range of
39–40°C and releases drug in a matter of seconds. Because
of the different attributes of the liposomes, it was possible to
delineate the relative importance of liposome drug encapsulation, HT
cytotoxicity, HT-drug interaction, HT-induced liposomal delivery, and
HT-triggered liposomal drug release in achieving antitumor activity.
Athymic nude mice bearing the FaDu human tumor xenograft were given a
single i.v. dose of 5 mg/kg of DOX (free drug or liposome
encapsulated), and the tumors were then heated to either 34°C or
42°C for 1 h at 34°C. All treatment groups were similar,
achieving low concentrations of DOX (0–4.5 ng/mg). At 42°C, the LTSL
(25.6 ng/mg) achieved the highest DOX concentration
(P < 0.04), but all three liposomal
formulations (7.3–25.6 ng/mg) were higher than saline or DOX (0–0.7
ng/mg; P < 0.02). LTSL + HT
was also the only group that resulted in significant amounts of
DNA-bound DOX (silver nitrate-extractable fraction;
P < 0.02). Tumor tissue sections were
visualized for DOX fluorescence to investigate the local distribution
of the drug in the tumor and confirm the relative drug concentrations
based on fluorescence intensity. There was relatively little
fluorescence seen with treatment groups at 34°C. At 42°C, the LTSL
showed the most DOX fluorescence (P < 0.01), and the fluorescence, although not homogeneous, was pervasive
throughout the tumor sections. Therapeutic efficacy of treatments was
determined from tumor growth time. At 34°C, the only treatment group
significantly better than the saline group (9.8 days) was the NTSL
group, with a growth time of 20.9 days (P < 0.02). At 42°C, all three liposomal formulations were more
efficacious than DOX. LTSL + HT had the longest growth time
(51.4 days) and the most number of local controls at 60 days (six of
nine tumors). With HT, the DOX concentrations and fluorescence were
tightly correlated with tumor growth delay, indicating that adequate
(increased) drug delivery can be predictive of therapeutic effect.
Overall, the LTSL + HT group showed the largest DOX
concentration, the highest and most pervasive DOX fluorescence, and the
most antitumor effect. Thus, HT-triggered liposomal drug release may
account for the largest differential therapeutic effect and
demonstrates the importance of rapid drug release from the drug
carriers at the tumor site.
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