Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-based Functional Materials and Devices, Soochow University, Suzhou, Jiangsu 215123, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidad, Taipa, Macau, China.
Biomaterials. 2017 Dec;148:69-80. doi: 10.1016/j.biomaterials.2017.09.021. Epub 2017 Sep 23.
The abnormal tumor vasculature is one of key reasons that lead to the limited tumor perfusion as well as hypoxic and immunosuppressive tumor microenvironment (TME). Herein, we uncover that by normalizing the tumor vasculature with erlotinib, a specific inhibitor of epidermal growth factor receptor (EGFR), the tumor perfusion and tumor oxygenation statuses in different types of tumors including murine breast tumors, colorectal tumors, and squamous cell carcinoma tumors, could be remarkably enhanced. As the results, the tumor uptake of drug-loaded nanoparticles as well as their interstitial penetration within the tumor would be greatly increased for mice pre-treated with erlotinib at the oral feeding dose of 50 mg/kg, leading to remarkably improved chemotherapeutic efficacy of nanomedicine. On the other hand, owing to the erlotinib-induced normalization of tumor vasculatures, the relieved hypoxic state in the three different types of tumors could alter the immunosuppressive TME into immunosupportive. Such an effect together with the increased tumor retention of anti-PDL1 antibody, a clinically approved checkpoint blockade agent, finally contributes to the greatly improved tumor inhibition effect in cancer immunotherapy. Therefore, our work presents a general yet effective strategy using a clinical drug to enhance the efficacies of cancer nanomedicine and immunotherapy by normalizing tumor vasculatures and modulating TME.
异常的肿瘤血管是导致肿瘤灌注有限以及缺氧和免疫抑制肿瘤微环境（TME）的关键原因之一。在这里，我们发现通过使用表皮生长因子受体（EGFR）的特异性抑制剂厄洛替尼使肿瘤血管正常化，可以显著增强包括鼠乳腺癌、结直肠癌和鳞状细胞癌在内的不同类型肿瘤的肿瘤灌注和肿瘤氧合状态。结果是，预先用厄洛替尼以 50mg/kg 的口服剂量处理的小鼠，其载药纳米颗粒的肿瘤摄取以及在肿瘤内的间质渗透都会大大增加，从而显著提高纳米医学的化疗疗效。另一方面，由于厄洛替尼诱导的肿瘤血管正常化，三种不同类型肿瘤中缓解的缺氧状态将免疫抑制的 TME 转变为免疫支持性。这种效应以及增加了临床批准的检查点抑制剂抗 PD-L1 抗体在肿瘤中的保留，最终有助于改善癌症免疫治疗中的肿瘤抑制效果。因此，我们的工作提出了一种通用且有效的策略，即使用临床药物通过使肿瘤血管正常化和调节 TME 来增强癌症纳米医学和免疫疗法的疗效。
