Mpekris Fotios, Voutouri Chrysovalantis, Panagi Myrofora, Baish James W, Jain Rakesh K, Stylianopoulos Triantafyllos
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus; Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
J Control Release. 2022 May;345:190-199. doi: 10.1016/j.jconrel.2022.03.008. Epub 2022 Mar 8.
Nanomedicine offered hope for improving the treatment of cancer but the survival benefits of the clinically approved nanomedicines are modest in many cases when compared to conventional chemotherapy. Metronomic therapy, defined as the frequent, low dose administration of chemotherapeutics - is being tested in clinical trials as an alternative to the conventional maximum tolerated dose (MTD) chemotherapy schedule. Although metronomic chemotherapy has not been clinically approved yet, it has shown better survival than MTD in many preclinical studies. When beneficial, metronomic therapy seems to be associated with normalization of the tumor microenvironment including improvements in tumor perfusion, tissue oxygenation and drug delivery as well as activation of the immune system. Recent preclinical studies suggest that nanomedicines can cause similar changes in the tumor microenvironment. Here, by employing a mathematical framework, we show that both approaches can serve as normalization strategies to enhance treatment. Furthermore, employing murine breast and fibrosarcoma tumor models as well as ultrasound shear wave elastography and contrast-enhanced ultrasound, we provide evidence that the approved nanomedicine Doxil can induce normalization in a dose-dependent manner by improving tumor perfusion as a result of tissue softening. Finally, we show that pretreatment with a normalizing dose of Doxil can improve the efficacy of immune checkpoint inhibition.
纳米医学为改善癌症治疗带来了希望，但与传统化疗相比，许多临床批准的纳米药物在提高生存率方面的益处并不显著。节拍疗法，即频繁、低剂量给药化疗药物，正在临床试验中作为传统最大耐受剂量（MTD）化疗方案的替代方法进行测试。尽管节拍化疗尚未获得临床批准，但在许多临床前研究中，它显示出比MTD更好的生存率。当产生有益效果时，节拍疗法似乎与肿瘤微环境的正常化有关，包括肿瘤灌注、组织氧合和药物递送的改善以及免疫系统的激活。最近的临床前研究表明，纳米药物可在肿瘤微环境中引起类似的变化。在此，通过采用一个数学框架，我们表明这两种方法都可作为增强治疗效果的正常化策略。此外，利用小鼠乳腺和纤维肉瘤肿瘤模型以及超声剪切波弹性成像和超声造影，我们提供证据表明，已获批的纳米药物阿霉素脂质体（Doxil）可通过组织软化改善肿瘤灌注，从而以剂量依赖的方式诱导肿瘤微环境正常化。最后，我们表明，用正常化剂量的阿霉素脂质体进行预处理可提高免疫检查点抑制的疗效。
