Combination radiofrequency (RF) ablation and IV liposomal heat shock protein suppression: reduced tumor growth and increased animal endpoint survival in a small animal tumor model.
BACKGROUND
To investigate the effect of IV liposomal quercetin (a known down-regulator of heat shock proteins) alone and with liposomal doxorubicin on tumor growth and end-point survival when combined with radiofrequency (RF) tumor ablation in a rat tumor model.


METHODS
Solitary subcutaneous R3230 mammary adenocarcinoma tumors (1.3-1.5 cm) were implanted in 48 female Fischer rats. Initially, 32 tumors (n=8, each group) were randomized into four experimental groups: (a) conventional monopolar RF alone (70°C for 5 min), (b) IV liposomal quercetin alone (1 mg/kg), (c) IV liposomal quercetin followed 24hr later with RF, and (d) no treatment. Next, 16 additional tumors were randomized into two groups (n=8, each) that received a combined RF and liposomal doxorubicin (15 min post-RF, 8 mg/kg) either with or without liposomal quercetin. Kaplan-Meier survival analysis was performed using a tumor diameter of 3.0 cm as the defined survival endpoint.


RESULTS
Differences in endpoint survival and tumor doubling time among the groups were highly significant (P<0.001). Endpoint survivals were 12.5±2.2 days for the control group, 16.6±2.9 days for tumors treated with RF alone, 15.5±2.1 days for tumors treated with liposomal quercetin alone, and 22.0±3.9 days with combined RF and quercetin. Additionally, combination quercetin/RF/doxorubicin therapy resulted in the longest survival (48.3±20.4 days), followed by RF/doxorubicin (29.9±3.8 days).


CONCLUSIONS
IV liposomal quercetin in combination with RF ablation reduces tumor growth rates and improves animal endpoint survival. Further increases in endpoint survival can be seen by adding an additional anti-tumor adjuvant agent liposomal doxorubicin. This suggests that targeting several post-ablation processes with multi-drug nanotherapies can increase overall ablation efficacy.
Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, USA.
Wei
W
Yang
Muneeb
M
Ahmed
Beenish
B
Tasawwar
Tatynana
T
Levchenko
Rupa R
RR
Sawant
Vladimir
V
Torchilin
S Nahum
SN
Goldberg
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D017115:Catheter Ablation; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004317:Doxorubicin / Q000008:administration & dosage; D023381:Endpoint Determination; D005260:Female; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D053208:Kaplan-Meier Estimate; D008081:Liposomes; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*; D011794:Quercetin / Q000008:administration & dosage; D051381:Rats; D013997:Time Factors
D006360:Heat-Shock Proteins; D008081:Liposomes; D004317:Doxorubicin; D011794:Quercetin