Key Laboratory of Marine Drugs, Ministry of Education & Shandong Provincial Key Laboratory of Glycoscience and Glycotechnology, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
Biomater Sci. 2020 Jan 1;8(1):189-200. doi: 10.1039/c9bm01604j. Epub 2019 Dec 10.
Hepatocellular carcinoma (HCC) patients suffer from severe pain due to the serious systemic side effects and low efficiency of chemotherapeutic drugs, and it is important to develop novel drug delivery systems to circumvent these issues. In this study, a series of galactose-based glycopolymers, poly(N-(prop-2-enoyl)-β-d-galactopyranosylamine)-b-poly(N-isopropyl acrylamide) (pGal(OH)-b-pNIPAA), were prepared through a sequential reversible addition-fragmentation chain transfer (RAFT) polymerization and tetrabutylammonium hydroxide (TBAOH)-mediated removal of acetyl groups. Hydrophilic doxorubicin hydrochloride was introduced to undergo collaborative assembly with poly(N-(prop-2-enoyl)-β-d-peracetylated galactosamine)-b-poly(N-isopropyl acrylamide) (pGal(Ac)-b-pNIPAA) via TBAOH treatment. pGal-b-pNIPAA/doxorubicin (DOX) delivery nanoparticles (GND NPs) formed by collaborative assembly were fully characterized by NMR, TEM and FT-IR, indicating the well-controlled formation of particles with uniform size and high efficiency in terms of drug loading and encapsulation compared with conventional adsorption methods. Meanwhile, the GND NPs were observed to be rapidly disintegrated under acidic conditions and resulted in an increased release of DOX. Cellular experiments showed that pGal-b-pNIPAA/DOX is apparently an asialoglycoprotein receptor (ASGPR)-mediated target of HCC, resulting in enhanced cellular uptake to HepG2 cells and anti-tumor efficacy in vitro. Furthermore, GND NPs III exerted more sustainable and effective anti-tumor effects compared to free DOX on a transgenic zebrafish TO(Kras) model in vivo. These results indicated that the biocompatible nanomaterials developed by collaborative assembly with galactosyl diblock glycopolymers and DOX may serve as a promising candidates for targeting therapy of HCC.
肝细胞癌（HCC）患者由于化疗药物的严重全身副作用和低效率而遭受严重疼痛，因此开发新的药物递送系统来规避这些问题非常重要。在这项研究中，通过顺序可逆加成-断裂链转移（RAFT）聚合和四丁基氢氧化铵（TBAOH）介导的乙酰基去除，制备了一系列基于半乳糖的糖聚合物，聚（N-（丙烯酰基）-β-D-半乳糖胺）-b-聚（N-异丙基丙烯酰胺）（pGal（OH）-b-pNIPAA）。亲水性盐酸多柔比星被引入到聚（N-（丙烯酰基）-β-D-全乙酰化半乳糖胺）-b-聚（N-异丙基丙烯酰胺）（pGal（Ac）-b-pNIPAA）中，通过 TBAOH 处理进行协同组装。通过 TBAOH 处理形成的协同组装的 pGal-b-pNIPAA/多柔比星（DOX）递药纳米颗粒（GND NPs）通过 NMR、TEM 和 FT-IR 进行了全面表征，表明与传统的吸附方法相比，颗粒的形成具有良好的控制，具有均匀的尺寸和高效的载药和包封。同时，在酸性条件下，GND NPs 被观察到迅速解体，导致 DOX 释放增加。细胞实验表明，pGal-b-pNIPAA/DOX 明显是肝细胞癌的去唾液酸糖蛋白受体（ASGPR）介导的靶点，导致 HepG2 细胞的摄取增加和体外抗肿瘤功效。此外，与游离 DOX 相比，GND NPs III 在体内转基因斑马鱼 TO（Kras）模型中表现出更持续和有效的抗肿瘤作用。这些结果表明，通过半乳糖二嵌段糖聚合物与 DOX 的协同组装开发的生物相容性纳米材料可能成为肝细胞癌靶向治疗的有前途的候选物。
