Li Hui, Liu Junwei, Wang Jingru, Li Zhuoyue, Yu Jianming, Huang Xu, Wan Bingchuan, Meng Xiangbao, Zhang Xuan
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
J Funct Biomater. 2024 Dec 9;15(12):372. doi: 10.3390/jfb15120372.
CY1-4, 9-nitropyridine [2',3':4,5] pyrimido [1,2-α] indole -5,11- dione, is an indoleamine 2,3-dioxygenase (IDO) inhibitor and a poorly water-soluble substance. It is very important to increase the solubility of CY1-4 to improve its bioavailability and therapeutic effect. In this study, the mesoporous silica nano-skeleton carrier material Sylysia was selected as the carrier to load CY1-4, and then the CY1-4 nano-skeleton drug delivery system (MSNM@CY1-4) was prepared by coating the hydrophilic polymer material Hydroxypropyl methylcellulose (HPMC) and the lipid material Distearoylphosphatidyl-ethanolamine-poly(ethylene glycol) (DSPE-PEG) to improve the anti-tumor effect of CY1-4. : The solubility and dissolution of MSNM@CY1-4 were investigated, and its bioavailability, anti-tumor efficacy, IDO inhibitory ability and immune mechanism were evaluated in vivo. : CY1-4 was loaded in MSNM@CY1-4 in an amorphous form, and MSNM@CY1-4 could significantly improve the solubility (up to about 200 times) and dissolution rate of CY1-4. In vivo studies showed that the oral bioavailability of CY1-4 in 20 mg/kg MSNM@CY1-4 was about 23.9-fold more than that in 50 mg/kg CY1-4 suspension. In B16F10 tumor-bearing mice, MSNM@CY1-4 significantly inhibited tumor growth, prolonged survival time, significantly inhibited IDO activity in blood and tumor tissues, and reduced Tregs in tumor tissues and tumor-draining lymph nodes to improve anti-tumor efficacy. : The nano-skeleton drug delivery system (MSNM@CY1-4) constructed in this study is a potential drug delivery platform for improving the anti-tumor effect of oral poorly water-soluble CY1-4.
CY1-4，即9-硝基吡啶[2',3':4,5]嘧啶并[1,2-α]吲哚-5,11-二酮，是一种吲哚胺2,3-双加氧酶（IDO）抑制剂，且水溶性较差。提高CY1-4的溶解度以改善其生物利用度和治疗效果非常重要。在本研究中，选择介孔二氧化硅纳米骨架载体材料Sylysia作为载体来负载CY1-4，然后通过包覆亲水性聚合物材料羟丙基甲基纤维素（HPMC）和脂质材料二硬脂酰磷脂酰乙醇胺-聚（乙二醇）（DSPE-PEG）制备CY1-4纳米骨架药物递送系统（MSNM@CY1-4），以提高CY1-4的抗肿瘤效果。研究了MSNM@CY1-4的溶解度和溶出度，并在体内评估了其生物利用度、抗肿瘤疗效、IDO抑制能力和免疫机制。CY1-4以无定形形式负载于MSNM@CY1-4中，MSNM@CY1-4可显著提高CY1-4的溶解度（高达约200倍）和溶出速率。体内研究表明，20mg/kg MSNM@CY1-4中CY1-4的口服生物利用度比50mg/kg CY1-4混悬液中的约高23.9倍。在荷B16F10肿瘤小鼠中，MSNM@CY1-4显著抑制肿瘤生长，延长生存时间，显著抑制血液和肿瘤组织中的IDO活性，并减少肿瘤组织和肿瘤引流淋巴结中的调节性T细胞以提高抗肿瘤疗效。本研究构建的纳米骨架药物递送系统（MSNM@CY1-4）是一种潜在的药物递送平台，可用于提高口服水溶性差的CY1-4的抗肿瘤效果。
