Controlled Drug Delivery to Colon Tumors Via Ultrasound

描述（由申请人提供）：强效化疗药物如多柔比星（Dox）的高毒性限制了其治疗窗口;然而，可以通过控制药物在空间（对肿瘤体积有选择性）和时间（释放的时机和持续时间）上的递送来扩大该窗口，使得周围组织不会受到不利影响。 我们最近的研究表明，超声波（US）可以控制从特殊的胶束载体（Plurogels）在体外释放的阿霉素。释放似乎也在大鼠肿瘤模型中体内发生，使得靶向肿瘤具有比双侧非靶向肿瘤更小的体积（p=0.006），并且心脏似乎免于Dox的心脏毒性。这些以前的研究是用低频超声完成的，很难聚焦。 本研究的目的是测试我们关于超声在引起药物释放中的作用的假设，并表明500 kHz超声可以聚焦以提供局部释放。体外研究将检验空化泡活动导致药物释放的假设。将测量空化活动的标记，并改变静压以证明空化的作用。大鼠的双侧肿瘤模型将显示是否可以用聚焦超声在体内实现局部释放。一个肿瘤将暴露于各种频率、强度和持续时间的超声，并且将测量两个肿瘤以确定哪些声学参数导致靶向肿瘤的选择性消退。我们还将测量心脏毒性，这是用Dox治疗时的常见副作用，但我们假设通过将Dox隔离在Plurogel载体中将其最小化。我们还将测试的假设，即空化活动扰乱细胞在焦点区域，这样的受声细胞采取更多的药物比其他。这样的细胞渗透也将与空化活性的标志物相关联，以验证空化的作用。研究结果将证明假设，这将成为理解和利用这种疗法治疗局部癌症的基础，有望为临床应用铺平道路。

DESCRIPTION (provided by applicant): The high toxicity of potent chemotherapeutic drugs like Doxorubicin (Dox) limit their therapeutic window; however, this window can be expanded by controlling the drug delivery in both space (selective to the tumor volume) and time (timing and duration of release) such that surrounding tissues are not adversely affected. Our recent research showed that ultrasound (US) can control the release of Dox from special micellar carriers (Plurogels) in vitro. The release appears to also occur in vivo in a rat tumor model such that a targeted tumor had smaller volume than a bilateral non-targeted tumor (p=0.006), and the heart appeared to be spared from the cardiotoxicity of Dox. These previous studies were done with low frequency ultrasound that is difficult to focus. The aims of this research are to test our hypotheses regarding the role of ultrasound in causing the drug release and show that 500 kHz ultrasound can be focused to provide local release. In vitro studies will test the hypothesis that cavitation bubble activity causes release of the drug. Markers of cavitational activity will be measured, and static pressure will be varied to prove the role of cavitation. A bilateral tumor model in rats will show whether localized release can be accomplished in vivo with focused ultrasound. One tumor will be exposed to ultrasound of various frequencies, intensities, and durations, and both tumors will be measured to determine which acoustic parameters cause selective regression of the targeted tumor. We will also measure cardiotoxicity, which is a common side effect when treating with Dox, but which we hypothesize will be minimized by sequestering the Dox in the Plurogel carrier. We will also test the hypothesis that cavitation activity perturbs cells in the focal region such that the insonated cells take up more drug than otherwise. Such cell permeation will also be correlated with markers of cavitational activity to verify the role of cavitation. The research outcomes will prove hypotheses, which will become the basis for understanding and exploiting this therapy in the treatment of localized cancers, hopefully paving the way for clinical application.