Microbubble-Assisted p53, RB, and p130 Gene Transfer in Combination with Radiation Therapy in Prostate Cancer

Rounak      Nande; Adelaide      Greco; Michael S.      Gossman; Jeffrey P.      Lopez; Luigi      Claudio; Marco      Salvatore; Arturo      Brunetti; James      Denvir; Candace M.      Howard; Pier Paolo      Claudio

doi:10.2174/1566523211313030001

Abstract

Combining radiation therapy and direct intratumoral (IT) injection of adenoviral vectors has been explored as a means to enhance the therapeutic potential of gene transfer. A major challenge for gene transfer is systemic delivery of nucleic acids directly into an affected tissue. Ultrasound (US) contrast agents (microbubbles) are viable candidates to enhance targeted delivery of systemically administered genes.

Here we show that p53, pRB, and p130 gene transfer mediated by US cavitation of microbubbles at the tumor site resulted in targeted gene transduction and increased reduction in tumor growth compared to DU-145 prostate cancer cell xenografts treated intratumorally with adenovirus (Ad) or radiation alone. Microbubble-assisted/US-mediated Ad.p53 and Ad.RB treated tumors showed significant reduction in tumor volume compared to Ad.p130 treated tumors (p<0.05). Additionally, US mediated microbubble delivery of p53 and RB combined with external beam radiation resulted in the most profound tumor reduction in DU-145 xenografted nude mice (p<0.05) compared to radiation alone. These findings highlight the potential therapeutic applications of this novel image-guided gene transfer technology in combination with external beam radiation for prostate cancer patients with therapy resistant disease.

Keywords: Retinoblastoma, RB, p130, p53, tumor suppressor gene, microbubbles, ultrasound, systemic targeted viral gene delivery, radiation, external beam radiation, apoptosis induction, prostate cancer.