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Target delivery selective CSF-1R inhibitor to tumor-associated macrophages via erythrocyte-cancer cell hybrid membrane camouflaged pH-responsive copolymer micelle for cancer immunotherapy.
European Journal of Pharmaceutical Sciences ( IF 4.6 ) Pub Date : 2019-11-05 , DOI: 10.1016/j.ejps.2019.105136
Yuchi Wang 1 , Zhiyong Luan 2 , Chaoyue Zhao 3 , Chunhua Bai 4 , Kangjuan Yang 5
Affiliation  

Tumor-associated macrophages (TAMs) is a promising therapeutic target for cancer immunotherapy, while TAMs targeting therapy using nano-sized drug delivery system (NDDS) is a great challenge. To overcome these drawbacks, a novel erythrocyte-cancer cell hybrid membrane camouflaged pH-responsive copolymer micelle (dextran-grafted-poly (histidine) copolymer) was prepared to target deliver a selective CSF-1R inhibitor: BLZ-945 (shorten as DH@ECm) to TAMs for TAMs depletion. The prepared DH@ECm possessed favorable particle size (~190 nm) preferable immune camouflage and tumor homologies targeting characteristic when it was intravenously administrated into blood system. In tumor acidic microenvironment, DH@ECm possessed pH-responsive characteristic and unique "membrane escape effect" to facilitate recognition and internalization by TAMs via dextran-CD206 receptor specific interaction (about 3.9 fold than free drug), followed by TAMs depletion in vitro. For in vivo studies, DH@ECm could reverse tumor immune-microenvironment with the elevation of CD8+ T cells and possess sufficient tumor immunotherapy (inhibition rate: 64.5%). All the in vitro and in vivo studies demonstrated the therapeutical potential of DH@ECm for tumor immunotherapy.

中文翻译:

通过红细胞-癌细胞混合膜伪装的pH响应共聚物胶束将选择性CSF-1R抑制剂靶向靶向肿瘤相关的巨噬细胞进行癌症免疫治疗。

肿瘤相关巨噬细胞(TAM)是癌症免疫疗法的有希望的治疗靶标,而使用纳米级药物递送系统(NDDS)的TAM靶向治疗则是一个巨大的挑战。为克服这些缺点,制备了一种新型的红细胞-癌细胞混合膜伪装的pH响应共聚物胶束(右旋糖酐接枝的聚(组氨酸)共聚物)以靶向释放选择性的CSF-1R抑制剂:BLZ-945(简称DH @ ECm)到TAM,以减少TAM。所制备的DH @ ECm静脉给药进入血液系统时,具有良好的粒径(〜190 nm),具有较好的免疫伪装和靶向肿瘤的同源性。在肿瘤酸性微环境中,DH @ ECm具有pH响应特性和独特的“膜逃逸作用”。促进TAM通过葡聚糖-CD206受体特异性相互作用(比游离药物约3.9倍)进行识别和内化,然后在体外消耗TAM。对于体内研究,DH @ ECm可随着CD8 + T细胞的升高而逆转肿瘤免疫微环境,并具有足够的肿瘤免疫疗法(抑制率:64.5%)。所有的体外和体内研究都证明了DH @ ECm在肿瘤免疫治疗中的治疗潜力。
更新日期:2019-11-05
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