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



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).



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).



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.
a Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology , Beth Israel Deaconess Medical Center/Harvard Medical School , Boston , Massachusetts , USA.
Marwan
M
Moussa
a Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology , Beth Israel Deaconess Medical Center/Harvard Medical School , Boston , Massachusetts , USA.|b Division of Image-Guided Therapy and Interventional Oncology, Department of Radiology , Hadassah Hebrew University Medical Center , Jerusalem , Israel.
S Nahum
SN
Goldberg
a Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology , Beth Israel Deaconess Medical Center/Harvard Medical School , Boston , Massachusetts , USA.
Gaurav
G
Kumar
c Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine , Northeastern University , Boston , Massachusetts , USA.
Tatyana
T
Levchenko
c Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine , Northeastern University , Boston , Massachusetts , USA.
Vladimir
V
Torchilin
a Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology , Beth Israel Deaconess Medical Center/Harvard Medical School , Boston , Massachusetts , USA.
Muneeb
M
Ahmed
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000627:therapeutic use; D017115:Catheter Ablation; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage* / Q000627:therapeutic use; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use; D011794:Quercetin / Q000008:administration & dosage* / Q000627:therapeutic use; D011916:Rats, Inbred F344
D000903:Antibiotics, Antineoplastic; D018840:HSP70 Heat-Shock Proteins; D008823:Micelles; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D011794:Quercetin
Thermal ablation; heat shock proteins; liposomal doxorubicin; liver; micelles; quercetin