Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of intratumoral chemotherapy using a novel approach comprising peri-tumoral injection of sustained-release liposomal nanoparticles containing phenylephrine, which is a potent vasoconstrictor. Using a preclinical model of melanoma, we have previously shown that systemically administered (intravenous) phenylephrine could transiently shunt blood flow to the tumor at the time of drug delivery, which in turn improved antitumor responses. This approach was called dynamic control of tumor-associated vessels. Herein, we used liposomal phenylephrine nanoparticles as a “local” dynamic control strategy for the B16 melanoma. Local dynamic control was shown to increase the retention and exposure time of tumors to intratumorally injected chemotherapy (melphalan). C57BL/6 mice bearing B16 tumors were treated with intratumoral melphalan and peri-tumoral injection of sustained-release liposomal phenylephrine nanoparticles (i.e., the local dynamic control protocol). These mice had statistically significantly improved antitumor responses compared to melphalan alone (p = 0.0011), whereby 58.3% obtained long-term complete clinical response. Our novel approach of local dynamic control demonstrated significantly enhanced antitumor efficacy and is the subject of future clinical trials being designed by our group.

中文翻译：

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脂质体去氧肾上腺素纳米颗粒增强黑色素瘤临床前模型中瘤内化疗的抗肿瘤活性

瘤内注射抗癌药物的功效有限，并且不常用于大多数癌症。在这项研究中，我们旨在使用一种新方法提高肿瘤内化疗的疗效，该方法包括在肿瘤周围注射含有去氧肾上腺素（一种有效的血管收缩剂）的缓释脂质体纳米颗粒。使用黑色素瘤的临床前模型，我们之前已经证明，全身注射（静脉注射）去氧肾上腺素可以在药物输送时暂时将血流分流到肿瘤，从而改善抗肿瘤反应。这种方法被称为肿瘤相关血管的动态控制。在此，我们使用脂质体去氧肾上腺素纳米颗粒作为 B16 黑色素瘤的“局部”动态控制策略。局部动态控制被证明可以增加肿瘤对瘤内注射化疗（美法仑）的保留和暴露时间。携带B16肿瘤的C57BL/6小鼠接受瘤内马法兰和瘤周注射缓释脂质体去氧肾上腺素纳米颗粒（即局部动态控制方案）治疗。与单独使用马法兰相比，这些小鼠的抗肿瘤反应在统计学上显着改善（p = 0.0011），其中 58.3% 获得了长期完全临床反应。我们的局部动态控制的新方法显示出显着增强的抗肿瘤功效，并且是我们小组未来设计的临床试验的主题。