Mao Yuling, Wang Xiudan, Chen Caishun, Zhao Qinfu, Liu Yanfeng, Zhang Jinghai, Wang Siling
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
School of Life Science and Bio-pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
Acta Pharm Sin B. 2022 Dec;12(12):4501-4518. doi: 10.1016/j.apsb.2022.04.018. Epub 2022 May 6.
Utilization of the intestinal lymphatic pathway will allow extraordinary gains in lymph and tumors cascade-targeted delivery of oral drugs and awakening the innate/adaptive immunity of the body and the lesion microenvironment, in addition to improving oral bioavailability relative to other means of delivery of oral drugs. Here, inspired by the specific invasion route of intestinal microorganisms, we pioneered an immune-awakening -inspired mesoporous silicon nanoparticle (yMSN) for the ingenious cascade-targeted delivery of therapeutic cancer vaccines and antitumor drugs to lymph and tumors the intestinal lymphatic pathway. Encouragingly, yMSN high-loaded tumor-specific antigens (OVA, 11.9%) and anti-tumor drugs (Len, 28.6%) with high stability, namely Len/OVA/yMSN, efficiently co-delivered OVA and Len to their desired target sites. Moreover, yMSN concomitantly awakened the innate antitumor immunity of dendritic cells and macrophages, strengthening vaccine-induced adaptive immune responses and reversing macrophage-associated immunosuppression in the tumor microenvironment. Surprisingly, Len/OVA/yMSN treatment resulted in excellent synergistic antitumor efficacy and long-term antitumor memory in OVA-Hepa1-6-bearing mice. This high-performance nanocarrier provides a novel approach for lesion-targeting delivery of oral drugs accompanied with awakening of the innate/adaptive immunity of the lesion environment, and also represents a novel path for the oral delivery of diverse therapeutic agents targeting other lymph-mediated diseases.
利用肠道淋巴途径不仅相对于其他口服给药方式提高口服生物利用度，还能实现淋巴和肿瘤对口服药物的级联靶向递送，并激活机体的先天/适应性免疫以及病变微环境。在此，受肠道微生物特定侵袭途径的启发，我们开创性地设计了一种免疫激活型介孔硅纳米颗粒（yMSN），用于将治疗性癌症疫苗和抗肿瘤药物巧妙地级联靶向递送至肠道淋巴途径的淋巴和肿瘤部位。令人鼓舞的是，yMSN能高负载肿瘤特异性抗原（OVA，11.9%）和抗肿瘤药物（Len，28.6%），且稳定性高，即Len/OVA/yMSN能有效地将OVA和Len共同递送至其预期靶位点。此外，yMSN能同时激活树突状细胞和巨噬细胞的先天抗肿瘤免疫，增强疫苗诱导的适应性免疫反应，并逆转肿瘤微环境中与巨噬细胞相关的免疫抑制。令人惊讶的是，Len/OVA/yMSN治疗在携带OVA-Hepa1-6的小鼠中产生了优异的协同抗肿瘤疗效和长期抗肿瘤记忆。这种高性能纳米载体为口服药物的病变靶向递送提供了一种新方法，同时伴随着病变环境先天/适应性免疫的激活，也为靶向其他淋巴介导疾病的多种治疗药物的口服递送开辟了一条新途径。
