Ultrasound guided site-specific gene delivery in prostate cancer

描述（由申请人提供）：该提案旨在通过使用由超声造影剂、病毒载体和超声波组成的创新系统来提高前列腺癌（PC）中基因递送的效率和特异性。此外，该提案旨在改善前列腺癌对放射治疗的反应。尽管现代放射技术在很大程度上改善了前列腺癌患者的预后，但常规放射治疗可能已经达到了最大获益。这一建议的影响在于这样一个事实，即基因如p130显着增加了3-照射后的凋亡细胞的百分比，潜在地改善前列腺癌的治疗。此外，超声造影剂提供靶向基因释放的优势，从而提高其特异性。微泡对基因治疗的影响是保护病毒载体免受免疫系统的快速降解，从而允许静脉注射而不是直接靶器官注射。超声造影剂（微泡）可以被设计成用作封装和递送遗传物质的安全载体。填充气体的微球有效地降低了空化的能量阈值。这允许诊断换能器在FDA规定的能量水平内工作，用于药物/基因输送。在超声处理区中，微泡经历空化，破坏气泡并释放其内容物。空化还产生小冲击波，增加细胞渗透性。这已经显示出在实验动物中增加由微泡共同递送的大分子或纳米球的跨毛细血管通过。该提案旨在改善前列腺癌放射治疗的结果。这些研究的结果将证明靶向p130基因递送是否是前列腺腺癌治疗中的有效辅助治疗，以及其使用是否可以降低治疗相关的发病率。这些实验的结果将成为未来患者临床试验的基础。 公共卫生相关性：该提案旨在通过使用由超声造影剂、病毒载体和超声波组成的创新系统来提高前列腺癌（PC）中基因递送的效率和特异性。此外，该提案旨在改善前列腺癌对放射治疗的反应。尽管现代放射技术在很大程度上改善了前列腺癌患者的预后，但常规放射治疗可能已经达到了最大获益。这一建议的影响在于这样一个事实，即基因如p130显着增加了3-照射后的凋亡细胞的百分比，潜在地改善前列腺癌的治疗。此外，超声造影剂提供靶向基因释放的优势，从而提高其特异性。微泡对基因治疗的影响是保护病毒载体免受免疫系统的快速降解，从而允许静脉注射而不是直接靶器官注射。此外，病毒是非特异性的。超声造影剂（微泡）可以被设计成用作封装和递送遗传物质的安全载体。填充气体的微球有效地降低了空化的能量阈值。这允许诊断换能器在FDA规定的能量水平内工作，用于药物/基因输送。在超声处理区中，微泡经历空化，破坏气泡并释放其内容物。空化还产生小冲击波，增加细胞渗透性。这已经显示出在实验动物中增加由微泡共同递送的大分子或纳米球的跨毛细血管通过。总之，该建议旨在改善前列腺癌放射治疗的结果。这些研究的结果将证明靶向p130基因递送是否是前列腺腺癌治疗中的有效辅助治疗，以及其使用是否可以降低治疗相关的发病率。这些实验的结果将成为未来患者临床试验的基础。

DESCRIPTION (provided by applicant): This proposal aims at improving the efficiency and specificity of gene delivery in prostate cancer (PC) by using an innovative system consisting of ultrasound contrast agents, viral vectors and ultrasound waves. Additionally, this proposal aims at improving the response of prostate cancer to radiation therapy. Despite the progress of modern radiation techniques in largely improving the prognosis of patients with prostate adenocarcinoma, the maximum benefit that can be achieved with conventional radiation therapy has probably been reached. The impact of this proposal lies in the fact that a gene such as p130 significantly increases the percentage of apoptotic cells after 3- irradiation potentially improving the treatment of prostate cancer. Additionally, ultrasound contrast agents offer the advantage of targeted gene release, thereby improving its specificity. The impact of microbubbles on gene therapy is to protect the viral vectors from rapid degradation by the immune system thus allowing for intravenous injection rather than direct target organ injection. Ultrasound contrast agents (microbubbles) may be designed to serve as safe vehicles to encapsulate and deliver genetic materials. The gas filled microspheres effectively lower the energy threshold for cavitation. This allows diagnostic transducers operating within the energy levels mandated by the FDA to be used for drug/gene delivery. In the sonification zone the microbubbles undergo cavitation, destroying the bubbles and releasing their contents. Cavitation also creates small shockwaves that increase cell permeability. This has been shown to increase transcapillary passage of macromolecules or nanoshperes codelivered by the microbubbles in experimental animals. This proposal aims at improving the outcome of radiation therapy in prostate cancer. The outcome of these studies will demonstrate whether targeted p130 gene delivery is an effective adjuvant treatment in the therapy of prostate adenocarcinoma and whether its use could be directed at decreasing treatment-related morbidity. The results of these experiments will be the basis for future patient clinical trials. PUBLIC HEALTH RELEVANCE: This proposal aims at improving the efficiency and specificity of gene delivery in prostate cancer (PC) by using an innovative system consisting of ultrasound contrast agents, viral vectors and ultrasound waves. Additionally, this proposal aims at improving the response of prostate cancer to radiation therapy. Despite the progress of modern radiation techniques in largely improving the prognosis of patients with prostate adenocarcinoma, the maximum benefit that can be achieved with conventional radiation therapy has probably been reached. The impact of this proposal lies in the fact that a gene such as p130 significantly increases the percentage of apoptotic cells after 3- irradiation potentially improving the treatment of prostate cancer. Additionally, ultrasound contrast agents offer the advantage of targeted gene release, thereby improving its specificity. The impact of microbubbles on gene therapy is to protect the viral vectors from rapid degradation by the immune system thus allowing for intravenous injection rather than direct target organ injection. Additionally, viruses are non-specific. Ultrasound contrast agents (microbubbles) may be designed to serve as safe vehicles to encapsulate and deliver genetic materials. The gas filled microspheres effectively lower the energy threshold for cavitation. This allows diagnostic transducers operating within the energy levels mandated by the FDA to be used for drug/gene delivery. In the sonification zone the microbubbles undergo cavitation, destroying the bubbles and releasing their contents. Cavitation also creates small shockwaves that increase cell permeability. This has been shown to increase transcapillary passage of macromolecules or nanoshperes codelivered by the microbubbles in experimental animals. In conclusion, this proposal aims at improving the outcome of radiation therapy in prostate cancer. The outcome of these studies will demonstrate whether targeted p130 gene delivery is an effective adjuvant treatment in the therapy of prostate adenocarcinoma and whether its use could be directed at decreasing treatment-related morbidity. The results of these experiments will be the basis for future patient clinical trials.