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Investigation of Enhancement of Gene Therapy with MR-Guided Focused Ultrasound (MRgHIFU)

L Chen1*, D Cvetkovic2 , C Ma3 , (1) Fox Chase Cancer Center, Philadelphia, PA, (2) Fox Chase Cancer Center, Philadelphia, PA, (3) Fox Chase Cancer Center, Philadelphia, PA


(Tuesday, 7/16/2019) 1:45 PM - 3:45 PM

Room: 303

Purpose: This study aims to investigate the feasibility of increasing the cellular uptake of AS-MDM2 with MRgHIFU to enhance the therapeutic effect of gene therapy.

Methods: Human prostate cancer cells LNCaP (5x105) were grown orthotopically in the prostates of 28 nude mice. Mice were divided randomly into 4 Groups (n=7/group): Group 1: MRgFU+AS-MDM2; Group 2: AS-MDM2 only; Group 3: MRgFU only; Group 4: control. When tumor grew to the size of 5-16 mm in maximum dimension mice were treated under general anesthesia with MRgHIFU at the acoustic power of 4 W, pulse width of 0.1 sec and 300 pulses in one sonication. Multiple sonications were used to cover the whole tumor volume. Immediately after the ultrasound treatment 0.1 ml of AS-MDM2, dissolved in PBS, was given by tail vein injection at doses 25 mg/kg for groups 1 and 2. Mice were sacrificed 6 and 24 hr after the injection of AS-MDM2 regardless of whether or not they were exposed to MRgHIFU. The tumors were processed for assessment of protein expression by immunohistochemical staining. The expression levels of MDM2, p53 and p21 proteins were quantified using an image-analysis system (ACIS, Chromavision Medical Systems, Inc., San Juan Capistrano, CA).

Results: Our results showed increased extravasations of blood cells treated with MRgFU + ASMDM2 injection as compared to that with ASMDM2 injection only. However, the expression levels of MDM2, p53 and p21 for both time points after treatment were not statistically significant.

Conclusion: One single AS-MDM injection may not be sufficient to knock down MDM2 or result in increases in p53 and p21. Since it is not clear whether the immunohistochemical staining results accurately reflected effects from AS-MDM2, further studies are being carried out on the effect of multiple MRgHIFU and AS-MDM2 treatments on the inhibition of LNCaP tumor growth.


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