Wu Hailiang, Tao Anqi, Martin John D, Quader Sabina, Liu Xueying, Takahashi Kei, Hespel Louise, Miura Yutaka, Hayakawa Yoshihiro, Irimura Tatsuro, Cabral Horacio, Kataoka Kazunori
Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14, Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
J Pharm Sci. 2017 Sep;106(9):2438-2446. doi: 10.1016/j.xphs.2017.03.031. Epub 2017 Apr 12.
Macrophage reprogramming toward a tumor-attacking phenotype is a promising treatment strategy, yet such strategies are scarce and it is not clear how to combine them with cytotoxic therapies that are often used to treat solid tumors. Here, we evaluate whether a micelle-encapsulated proteasome inhibitor, that is, the peptide aldehyde drug MG132, which is cytotoxic to cancer cells, can reprogram macrophages to attack the tumor. Through in vitro studies, we demonstrated that the proteasome inhibition reduces nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling-a known promoter of tumor-supporting macrophages and chemoresistance-in both cancer cells and macrophages. In in vivo studies, we showed that, although free MG132 did not affect the macrophage phenotype in tumors even at its maximum tolerated dose, the micellar formulation of MG132 safely achieved simultaneous cancer cell killing and macrophage reprogramming, thereby enhancing the antitumor efficacy in a syngeneic, orthotopic breast cancer model.
将巨噬细胞重编程为具有肿瘤攻击表型是一种很有前景的治疗策略，但此类策略很少见，并且尚不清楚如何将它们与常用于治疗实体瘤的细胞毒性疗法相结合。在此，我们评估一种胶束包裹的蛋白酶体抑制剂，即对癌细胞具有细胞毒性的肽醛药物MG132，是否能够重编程巨噬细胞以攻击肿瘤。通过体外研究，我们证明蛋白酶体抑制可降低活化B细胞核因子κB（NF-κB）信号传导——这是肿瘤支持性巨噬细胞和化疗耐药性的已知促进因子——在癌细胞和巨噬细胞中均如此。在体内研究中，我们表明，尽管游离的MG132即使在其最大耐受剂量下也不会影响肿瘤中的巨噬细胞表型，但MG132的胶束制剂可安全地同时实现癌细胞杀伤和巨噬细胞重编程，从而在同基因原位乳腺癌模型中提高抗肿瘤疗效。
