College of Pharmaceutical Sciences, Zhejiang University of Technology, No. 1 Gongda Road, Hangzhou, 313000, People's Republic of China.
J Nanobiotechnology. 2022 Sep 5;20(1):402. doi: 10.1186/s12951-022-01596-2.
7-p-trifluoromethylphenyl-FL118 (FLQY2) is a camptothecin analog with excellent antitumor efficacy against various solid tumors. However, its poor solubility and low bioavailability limited the development of the drug. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), an emerging carrier for preparing solid dispersion (SD), encapsulated FLQY2 to circumvent the above limitations.
In this project, FLQY2-SD was prepared by solvent evaporation method and self-assembled into micelles in aqueous solutions owing to the amphiphilic nature of Soluplus. The physicochemical characterizations demonstrated that FLQY2 existed in a homogeneous amorphous form in SD and was rapidly dissolved. The micelles did not affect cytotoxicity or cellular uptake of FLQY2 in vitro, and the oral bioavailability was increased by 12.3-fold compared to the FLQY2 cyclodextrin suspension. The pharmacokinetics of FLQY2-SD showed rapid absorption, accumulation in the intestine, and slow elimination via fecal. Metabolite identification studies showed 14 novel metabolites were identified, including 12 phase I metabolites (M1-M12) and 2 phase II metabolites (M13-M14), of which M2 (oxidation after decarboxylation) and M7 (dioxolane ring cleavage) were the primary metabolites in the positive mode and negative mode, respectively. The tumor growth inhibition rate (TGI, 81.1%) of FLQY2-SD (1.5 mpk, p.o./QW) in tumor-bearing mice after oral administration was higher than that of albumin-bound Paclitaxel (15 mpk, i.v./Q4D) and Irinotecan hydrochloride (100 mpk, i.p./QW).
The successful preparation, pharmacokinetics, and pharmacodynamics studies of FLQY2-SD showed that the solubility and bioavailability of FLQY2 were improved, which facilitated the further druggability development of FLQY2.
7-对三氟甲基苯基-FL118(FLQY2)是一种喜树碱类似物,对各种实体瘤具有优异的抗肿瘤疗效。然而,其较差的溶解度和低生物利用度限制了该药物的发展。聚乙烯吡咯烷酮-醋酸乙烯酯-聚乙二醇接枝共聚物(Soluplus)是一种新兴的制备固体分散体(SD)的载体,可以将 FLQY2 包裹起来以克服上述限制。
在本项目中,FLQY2-SD 通过溶剂蒸发法制备,并由于 Soluplus 的两亲性而在水溶液中自组装成胶束。理化性质研究表明,SD 中 FLQY2 以均匀的无定形形式存在,且迅速溶解。体外实验表明,胶束不影响 FLQY2 的细胞毒性或摄取,与 FLQY2 环糊精混悬剂相比,口服生物利用度提高了 12.3 倍。FLQY2-SD 的药代动力学研究表明,其吸收迅速,在肠道中积累,通过粪便缓慢消除。代谢产物鉴定研究表明,共鉴定出 14 种新的代谢产物,包括 12 种 I 相代谢产物(M1-M12)和 2 种 II 相代谢产物(M13-M14),其中 M2(脱羧后氧化)和 M7(二氧戊环环裂解)分别为正模式和负模式下的主要代谢产物。口服给予 FLQY2-SD(1.5mpk,p.o./QW)后,荷瘤小鼠的肿瘤生长抑制率(TGI,81.1%)高于白蛋白结合紫杉醇(15mpk,i.v./Q4D)和盐酸伊立替康(100mpk,i.p./QW)。
FLQY2-SD 的成功制备、药代动力学和药效学研究表明,FLQY2 的溶解度和生物利用度得到了提高,这有助于进一步开发 FLQY2 的成药性。