新型 SN38 衍生物脂质体作为抗癌前药的研究：体外与体内研究。

BACKGROUND: Many novel drug delivery systems have been extensively studied to exploit the full therapeutic potential of SN38, which is one of the most potent antitumor analogs of camptothecins (CPTs), whose clinical application is seriously hindered by poor water solubility, low plasmatic stability, and severe toxicity, but results are always unsatisfactory. METHODS: In this study, combining the advantages of prodrug and nanotechnology, a lipophilic prodrug of SN38, SN38-PA, was developed by conjugating palmitic acid to SN38 via ester bond at C position, and then the lipophilic prodrug was encapsulated into a long-circulating liposomal carrier by film dispersion method. RESULTS: The SN38-PA liposomes were characterized as follows: an average particle size of 80.13 nm, an average zeta potential of -33.53 mv, and the entrapment efficiency of 99%. Compared with CPT-11, SN38-PA liposome was more stable in close lactone form, more efficient in conversion rate to SN38, and more potent in cytotoxicity against tumor cells. Pharmacokinetic study showed that SN38-PA liposome had significantly enhanced plasma half-life (t) value of SN38 and increased area under the curve (AUC) of SN38, which was 7.5-fold higher than that of CPT-11. Biodistribution study showed that SN38-PA liposome had more active metabolite SN38 in each tissue. Finally, the pharmacodynamic study showed that SN38-PA liposome had higher antitumor effect with the antitumor inhibition rate of 1.61 times than that of CPT-11. CONCLUSION: These encouraging data merit further investigation on this novel SN38-PA liposome.

背景：许多新型药物递送系统已被广泛研究，以充分发挥 SN38 的治疗潜力，SN38 是喜树碱（CPTs）类中最有效的抗肿瘤类似物之一，但其临床应用受到水溶性差、血浆稳定性低和毒性严重等因素的严重阻碍，但结果总是不尽人意。

方法：在本研究中，结合前药和纳米技术的优势，通过在 C 位将棕榈酸与 SN38 酯化，将 SN38 前药 SN38-PA 合成，然后通过薄膜分散法将亲脂性前药包封到长循环脂质体载体中。

结果：SN38-PA 脂质体的特征如下：平均粒径为 80.13nm，平均 zeta 电位为-33.53mv，包封率为 99%。与 CPT-11 相比，SN38-PA 脂质体更稳定地处于内酯形式，SN38 的转化率更高，对肿瘤细胞的细胞毒性更强。药代动力学研究表明，SN38-PA 脂质体显著提高了 SN38 的血浆半衰期（t）值，增加了 SN38 的曲线下面积（AUC），是 CPT-11 的 7.5 倍。生物分布研究表明，SN38-PA 脂质体在每个组织中都具有更活跃的代谢物 SN38。最后，药效学研究表明，SN38-PA 脂质体具有更高的抗肿瘤作用，其抗肿瘤抑制率比 CPT-11 高 1.61 倍。

结论：这些令人鼓舞的数据表明，这种新型 SN38-PA 脂质体值得进一步研究。