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

摘要

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 24 hr 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.