Effect of thermal dose on heat shock protein expression after radio-frequency ablation with and without adjuvant nanoparticle chemotherapies

Abstract

Purpose: The aim of this study was to evaluate the effect of different radio-frequency ablation (RFA) thermal doses on coagulation and heat shock protein (HSP) response with and without adjuvant nanotherapies.

Materials and methods: First, Fischer rats were assigned to nine different thermal doses of hepatic RFA (50–90 °C, 2–20 min, three per group) or no treatment (n = 3). Next, five of these RF thermal doses were combined with liposomal-doxorubicin (Lipo-Dox, 1 mg intravenously) in R3230 breast tumours, or no tumour treatment (five per group). Finally, RFA/Lipo-Dox was given without and with an Hsp70 inhibitor, micellar quercetin (Mic-Qu, 0.3 mg intravenously) for two different RFA doses with similar coagulation but differing peri-ablational Hsp70 (RFA/Lipo-Dox at 70 °C × 5 min and 90 °C × 2 min, single tumours, five per group). All animals were sacrificed 24 h post-RFA and gross tissue coagulation and Hsp70 (maximum rim thickness and % cell positivity) were correlated to thermal dose including cumulative equivalent minutes at 43 °C (CEM₄₃).

Results: Incremental increases in thermal dose (CEM₄₃) correlated to increasing liver tissue coagulation (R² = 0.7), but not with peri-ablational Hsp70 expression (R² = 0.14). Similarly, increasing thermal dose correlated to increasing R3230 tumour coagulation for RF alone and RFA/Lipo-Dox (R² = 0.7 for both). The addition of Lipo-Dox better correlated to increasing Hsp70 expression compared to RFA alone (RFA: R² = 0.4, RFA/Lipo-Dox: R² = 0.7). Finally, addition of Mic-Qu to two thermal doses combined with Lipo-Dox resulted in greater tumour coagulation (p < 0.0003) for RFA at 90 °C × 2 min (i.e. greater baseline Hsp70 expression) than an RFA dose that produced similar coagulation but less HSP expression (p < 0.0004).

Conclusion: Adjuvant intravenous Lipo-Dox increases peri-ablational Hsp70 expression in a thermally dependent manner. Such expression can be exploited to produce greater tumour destruction when adding a second adjuvant nanodrug (Mic-Qu) to suppress peri-ablational HSP expression.

Keywords:

• Thermal ablation
• heat shock proteins
• liver
• micelles
• quercetin
• liposomal doxorubicin

Disclosure statement

The authors report no other conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Funding information

This study was supported by grants from the National Cancer Institute, Bethesda, MD (CCNE1U54CA151881-01), the Harvard Medical Faculty Physicians Radiology Foundation, and the Israel Research Foundation/Israel Ministry of Health.