High intensity focused ultrasound-induced gene activation in solid tumors.
In this work, the activation of heat-sensitive trans-gene by high-intensity focused ultrasound (HIFU) in a tumor model was investigated. 4T1 cancer cells (2 x 10(6)) were inoculated subcutaneously in the hind limbs of Balb/C mice. The tumors were subsequently transducted on day 10 by intratumoral injection of a heat-sensitive adenovirus vector (Adeno-hsp70B-Luc at 2 x 10(8) pfu/tumor). On day 11, the tumors were heated to a peak temperature of 55, 65, 75, or 85 degrees C within 10-30 s at multiple sites around the center of the tumor by a 1.1- or 3.3-MHz HIFU transducer. Inducible luciferase gene expression was increased from 15-fold to 120-fold of the control group following 1.1-MHz HIFU exposure. Maximum gene activation (120-fold) was produced at a peak temperature of 65-75 degrees C one day following HIFU exposure and decayed to baseline within 7 days. HIFU-induced gene activation (75 degrees C-10 s) could be further improved by using a 3.3-MHz transducer and a dense scan strategy to 170-fold. Thermal stress, rather than nonthermal mechanical stress, was identified as the primary physical mechanism for HIFU-induced gene activation in vivo. Overall, these observations open up the possibility for combining HIFU thermal ablation with heat-regulated gene therapy for cancer treatment.
Liu
Yunbo
Y
Department of Mechanical Engineering and Materials Science, Duke University, Durham, North Carolina 27708, USA.
Kon
Takashi
T
Li
Chuanyuan
C
Zhong
Pei
P
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D041722:Genes, Transgenic, Suicide / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics; D006979:Hyperthermia, Induced / Q000295:instrumentation / Q000379:methods*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D049408:Luminescent Agents / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000235:genetics / Q000628:therapy*; D011401:Promoter Regions, Genetic; D013314:Stress, Mechanical; D015533:Transcriptional Activation; D014463:Ultrasonography
D018840:HSP70 Heat-Shock Proteins; C491129:HSPA7 protein, human; D049408:Luminescent Agents; D008156:Luciferases