a Shengjing Hospital, China Medical University , Shenyang , China.
Drug Deliv. 2019 Dec;26(1):756-764. doi: 10.1080/10717544.2019.1642418.
Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer.
肿瘤微环境与肝癌的发生发展密切相关。肿瘤相关巨噬细胞（TAMs）是肿瘤微环境的重要组成部分，通过抑制免疫细胞促进肿瘤恶化和转移。先前的研究表明，PI3Kγ 抑制剂可以逆转 TAMs 的表型，缓解免疫抑制并使化疗药物敏感，这表明 PI3Kγ 抑制剂与化疗药物的联合可能在肝癌治疗中带来新的突破。基于此，本文构建了具有肿瘤微环境响应性的 HES-TG100-115-CDM-PEG 胶束，同时负载索拉非尼和 TG100-115，协同治疗肝癌。药代动力学研究表明，与游离药物溶液相比，制备的胶束具有更长的半衰期，有利于通过肿瘤血管窗孔的高渗透性外渗。在低 pH 和高 α-淀粉酶还原条件下，由于键的敏感性，胶束会迅速解聚，并显著增强对 Hep-3B 肝癌细胞的细胞毒性活性。此外，与游离药物溶液相比，胶束对荷 Hep-3B 细胞的裸鼠表现出更高的抗肿瘤效率和更好的耐受性。这些发现表明 HES-TG100-115-CDM-PEG 胶束是肝癌临床综合治疗中有前途的药物递送系统。
