Microbubble-enhanced ultrasound for gene therapy

Prostate cancer is a very heterogeneous disease marked by varying rates of progression and response to therapies. Organ-confined tumors can be cured by surgical removal of the prostate, whereas for late stage tumors that escaped androgen ablation therapy only palliative treatments are available. Due to widespread use of PSA screening for early diagnosis of prostate cancer, the detection rate of organ-confined tumors has increased but currently only aggressive and/or highly invasive radical prostatectomy or radiation can be offered in this case, even if the tumor is very small. Besides watchful waiting alternative less-aggressive treatment is not available. Thus, there is an urgent need for the establishment of new therapies. Since the androgen receptor (AR) is a key regulatory element in both, androgen-dependent as well as advanced androgen-independent prostate tumors, we have recently developed a strategy to inhibit AR expression with antisense molecules, which result in inhibition of prostate tumor cell growth in vitro as well as in vivo. Despite these promising results, a crucial problem remains to be solved before this therapy can be applied in patients: an efficient and specific system for delivery of antisense molecules into prostate tumor cells. Our project will focus on the development of microbubble-enhanced ultrasound for the delivery of antisense AR molecules to prostate tumor tissue. Microbubbles work as carriers, in that they are loaded with the antisense molecules on their lipid surface. Due to their gas-filled interior, they can be visualized by ultrasound in the tissue and destroyed by an ultrasound pulse whereupon the genetic material is specifically released at the target site. Attachment of antisense molecules to the microbubbles is achieved by ion charge binding. We want to test the usefulness of this method and establish the basis for the use of this concept for prostate cancer therapy in the future. Two different prostate cancer models will be employed in vitro as well as in vivo. One will be the LNCaP prostate cancer model and the other will be the androgen-ablated LNCaPabl model, which represents tumor cells after long- term androgen-ablation therapy. With the use of contrast agent microbubbles loaded with antisense molecules against the AR, we expect to develop a new gene-therapeutic approach for prostate cancer. This may represent an alternative therapy for patients with very small tumors instead of radical prostatectomy but also for advanced metastatic prostate tumors, which are resistant to hormone ablation.

Prostate cancer is a very heterogeneous disease marked by varying rates of progression and response to therapies. Organ-confined tumors can be cured by surgical removal of the prostate, whereas for late stage tumors that escaped androgen ablation therapy only palliative treatments are available. Due to widespread use of PSA screening for early diagnosis of prostate cancer, the detection rate of organ-confined tumors has increased but currently only aggressive and/or highly invasive radical prostatectomy or radiation can be offered in this case, even if the tumor is very small. Besides watchful waiting alternative less-aggressive treatment is not available. Thus, there is an urgent need for the establishment of new therapies. Since the androgen receptor (AR) is a key regulatory element in both, androgen-dependent as well as advanced androgen-independent prostate tumors, we have recently developed a strategy to inhibit AR expression with antisense molecules, which result in inhibition of prostate tumor cell growth in vitro as well as in vivo. Despite these promising results, a crucial problem remains to be solved before this therapy can be applied in patients: an efficient and specific system for delivery of antisense molecules into prostate tumor cells. Our project will focus on the development of microbubble-enhanced ultrasound for the delivery of antisense AR molecules to prostate tumor tissue. Microbubbles work as carriers, in that they are loaded with the antisense molecules on their lipid surface. Due to their gas-filled interior, they can be visualized by ultrasound in the tissue and destroyed by an ultrasound pulse whereupon the genetic material is specifically released at the target site. Attachment of antisense molecules to the microbubbles is achieved by ion charge binding. We want to test the usefulness of this method and establish the basis for the use of this concept for prostate cancer therapy in the future. Two different prostate cancer models will be employed in vitro as well as in vivo. One will be the LNCaP prostate cancer model and the other will be the androgen-ablated LNCaPabl model, which represents tumor cells after long-term androgen-ablation therapy. With the use of contrast agent microbubbles loaded with antisense molecules against the AR, we expect to develop a new gene-therapeutic approach for prostate cancer. This may represent an alternative therapy for patients with very small tumors instead of radical prostatectomy but also for advanced metastatic prostate tumors, which are resistant to hormone ablation.