Controlled Drug Delivery to Colon Tumors Via Ultrasound

描述(申请人提供)：强力化疗药物如多柔比星(Dox)的高毒性限制了它们的治疗窗口；然而，可以通过控制药物在空间(对肿瘤体积的选择性)和时间(释放时间和持续时间)上的给药来扩大治疗窗口，以使周围组织不受不利影响。我们最近的研究表明，超声波(US)可以控制Dox从特殊胶束载体(Plurogels)中的体外释放。这种释放似乎也发生在体内的大鼠肿瘤模型中，靶向肿瘤的体积比双侧非靶向肿瘤小(p=0.006)，心脏似乎不受多柔比星的心脏毒性。这些先前的研究都是使用难以聚焦的低频超声波进行的。 这项研究的目的是测试我们关于超声波在药物释放中的作用的假设，并表明500 kHz的超声波可以聚焦以提供局部释放。体外研究将检验空化气泡活动导致药物释放的假设。将测量空化活动的标志，并改变静压以证明空化的作用。大鼠双侧肿瘤模型将显示聚焦超声能否在体内实现局部释放。其中一个肿瘤将被暴露在不同频率、强度和持续时间的超声波下，两个肿瘤都将被测量，以确定哪些声学参数导致目标肿瘤的选择性消退。我们还将测量心脏毒性，这是使用Dox治疗时的常见副作用，但我们假设通过将Dox隔离在PluroGel载体中将其降至最低。我们还将测试空化活动扰乱焦点区域细胞的假设，从而使受辐射的细胞比其他细胞吸收更多的药物。这样的细胞渗透也将与空化活动的标志相关联，以验证空化的作用。研究结果将证明假说，这将成为了解和利用这一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.