A site-oriented nanosystem for active transcellular chemo-immunotherapy to prevent tumor growth and metastasis

主动穿细胞转运的定向纳米载体用于化学-免疫治疗抑制肿瘤生长及转移

Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapyenhanced immunotherapy. When arriving at the tumor site,the matrix metallopeptidase 2(MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and siteoriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues,recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.

目前免疫治疗已经显示出了极大的肿瘤治疗潜力,然而纳米载体较低的转运能力以及肿瘤免疫响应性低等问题严重阻碍了免疫治疗的临床应用.为了解决这些问题,本课题研制了一种具有主动穿细胞转运能力的定向纳米载体用于化疗增强的免疫治疗.当该纳米载药系统到达肿瘤部位,金属基质蛋白酶2响应的纳米外壳崩解,释放出带有正电荷的纳米内核.正电荷促使纳米内核产生吸附介导的胞吞,进而促进纳米载药系统的跨血管内皮细胞运输和跨细胞药物递送,并最终将药物递送到远端肿瘤细胞中. PD-L1抗体和化疗药物分别被载于纳米载体的外壳和内核中进行精准递送,从而达到对具有不同治疗靶点的药物同步递送、定向释药的目的.肿瘤微环境中释放的PD-L1抗体作用于T细胞表面的特异性受体,阻断了T细胞与肿瘤细胞的结合.正电荷纳米内核同步运载奥沙利铂和吲哚美辛进入深层肿瘤细胞,在整个肿瘤组织中引发免疫原性死亡、逆转免疫抑制作用,招募大量的T细胞并最终增强免疫治疗疗效.本研究中所构建的纳米载药体系不仅能够抑制原位瘤生长,还能够阻止肿瘤的转移.这为化疗增强的免疫治疗提供了一种新的纳米递送方案,提高了免疫治疗在免疫响应率低的肿瘤中的疗效.