Controlled Drug Delivery to Colon Tumors Via Ultrasound

描述（由申请人提供）：强效化疗药物如阿霉素（Dox）的高毒性限制了它们的治疗窗口；然而，这个窗口期可以通过控制药物在空间（选择性肿瘤体积）和时间（释放的时间和持续时间）上的传递来扩大，这样就不会对周围组织产生不利影响。我们最近的研究表明，超声（US）可以控制Dox从特殊胶束载体（Plurogels）的体外释放。在体内的大鼠肿瘤模型中，释放似乎也发生了，因此靶肿瘤的体积比双侧非靶肿瘤小（p=0.006），心脏似乎免受Dox的心脏毒性影响。这些先前的研究是用低频超声完成的，很难聚焦。

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.