State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
Eur J Pharm Sci. 2018 Jul 1;119:121-134. doi: 10.1016/j.ejps.2018.04.011. Epub 2018 Apr 7.
Curcumin (CUR) is a natural diketone with diverse bioactivities of inhibiting angiogenesis and tumor growth. However, its clinical application for cancer treatment was severely hindered by poor aqueous solubility and chemical instability. To overcome these drawbacks and achieve enhanced antitumor efficiency, low molecular weight heparin (LMWH) was conjugated to CUR via the one-step esterification reaction to yield LMWH-CUR (LCU) nanodrugs with the size of 180 nm, which exhibited enhanced accumulation within tumor site by EPR effect and long circulating capacity by LMWH hydrophilic shell. The solubility of conjugated CUR was increased to 0.12 mg/mL (equivalent of CUR) in comparison with 0.006 mg/mL of free CUR. The bioactivities of CUR were guaranteed because of the improved stability of LCU nanodrugs in low pH condition. Moreover, the stronger anti-angiogenesis efficacy of LCU nanodrugs than LMWH monotherapy was also verified. Notably, at a rather low dose of equivalent LMWH (5 mg/kg) and CUR (0.3 mg/kg), the tumor inhibition rate of LCU nanodrugs were much higher than that of LMWH (10 times) and LMWH plus CUR mixture (3.8 times) respectively, indicating its excellent in vivo antitumor efficacy. Overall, our study managed to obtain the novel nanodrugs with potent anti-angiogenesis and antitumor effects whereas avoiding tedious and complicated synthetic procedures. These results also suggested that LCU nanodrugs could be considered as a promising targeted delivery system for cancer treatment.
姜黄素（CUR）是一种具有抑制血管生成和肿瘤生长等多种生物活性的天然二酮。然而，由于其较差的水溶性和化学不稳定性，其在癌症治疗方面的临床应用受到了严重限制。为了克服这些缺点并提高抗肿瘤效率，通过一步酯化反应将低分子量肝素（LMWH）与 CUR 连接，得到了尺寸为 180nm 的 LMWH-CUR（LCU）纳米药物，通过 EPR 效应增强了在肿瘤部位的积累，并通过 LMWH 亲水壳延长了循环时间。与游离 CUR 的 0.006mg/mL（相当于 CUR）相比，共轭 CUR 的溶解度提高到了 0.12mg/mL。由于 LCU 纳米药物在低 pH 条件下的稳定性提高，保证了 CUR 的生物活性。此外，还验证了 LCU 纳米药物比 LMWH 单药治疗具有更强的抗血管生成作用。值得注意的是，在相当低的剂量（相当于 LMWH 5mg/kg 和 CUR 0.3mg/kg）下，LCU 纳米药物的肿瘤抑制率明显高于 LMWH（10 倍）和 LMWH 加 CUR 混合物（3.8 倍），表明其具有优异的体内抗肿瘤疗效。总的来说，本研究成功获得了具有强大抗血管生成和抗肿瘤作用的新型纳米药物，同时避免了繁琐复杂的合成步骤。这些结果还表明，LCU 纳米药物可以被认为是一种有前途的癌症治疗靶向递送系统。
