Shi Yongli, Pan Xiaofei, Xu Suyue, Zhu Huiqing, Zhao Bingqian, Sun Zeyu, Dong Ruoyi, Li Na, Hou Xueyan, Yang Xue
College of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, PR China.
College of Pharmacy, Xinxiang Medical University, 453003, Xinxiang, PR China.
Eur J Med Chem. 2023 Nov 15;260:115715. doi: 10.1016/j.ejmech.2023.115715. Epub 2023 Aug 9.
The purpose of this study was to synthesize DHPD polymers through the conjugation of doxorubicin (DOX) molecules onto poly(ethylene glycol) (PEG) chains via acylhydrazone bonds, and to fabricate pH-responsive DHPD nanoparticles (NPs) for investigation of their biosecurity and in vivo anti-tumor activity. The morphology, size distribution, stability, pH-responsiveness, biosecurity, and in vivo anti-tumor effects of the DHPD NPs were evaluated. Characterization of the DHPD polymers using H NMR, FTIR, and Raman spectra confirmed their successful synthesis. The DHPD NPs exhibited a round morphology with an average diameter of 144.4 ± 1.7 nm and a polydispersity index (PDI) of 0.23 ± 0.02. Biosecurity studies indicated that the DHPD NPs were non-toxic to treated mice, and in vitro cell tests demonstrated their ability to be taken up by 4T1 cells. Under the acidic microenvironment of 4T1 cells, the acylhydrazone bonds were cleaved, resulting in increased DOX delivery to tumor cells and improved in vivo anti-tumor effects. Animal experiments confirmed that the DHPD NPs reduced DOX toxicity while enhancing its anti-tumor activity. Furthermore, results from the analysis of γ-interferon (INF-γ), tumor necrosis factor-α (TNF-α), epidermal growth factor (EGF), and vascular endothelial growth factor (VEGF) indicated that the DHPD NPs improved the anti-4T1 tumor effect of DOX, suggesting their potential application in the treatment of breast cancer.
本研究的目的是通过腙键将阿霉素（DOX）分子缀合到聚乙二醇（PEG）链上，合成DHPD聚合物，并制备pH响应性DHPD纳米颗粒（NPs），以研究其生物安全性和体内抗肿瘤活性。对DHPD NPs的形态、尺寸分布、稳定性、pH响应性、生物安全性和体内抗肿瘤效果进行了评估。使用1H NMR、FTIR和拉曼光谱对DHPD聚合物进行表征，证实了它们的成功合成。DHPD NPs呈现圆形形态，平均直径为144.4±1.7 nm，多分散指数（PDI）为0.23±0.02。生物安全性研究表明，DHPD NPs对处理过的小鼠无毒，体外细胞试验证明它们能够被4T1细胞摄取。在4T1细胞的酸性微环境下，腙键被裂解，导致DOX向肿瘤细胞的递送增加，体内抗肿瘤效果得到改善。动物实验证实，DHPD NPs降低了DOX的毒性，同时增强了其抗肿瘤活性。此外，对γ干扰素（INF-γ）、肿瘤坏死因子-α（TNF-α）、表皮生长因子（EGF）和血管内皮生长因子（VEGF）的分析结果表明，DHPD NPs提高了DOX对4T1肿瘤的治疗效果，表明它们在乳腺癌治疗中的潜在应用价值。
