Hagiwara Yoshiyuki, Arima Hidetoshi, Miyamoto Yuji, Hirayama Fumitoshi, Uekama Kaneto
Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi, Japan.
Chem Pharm Bull (Tokyo). 2006 Jan;54(1):26-32. doi: 10.1248/cpb.54.26.
To evaluate the potential use of a drug/cyclodextrin (CyD) conjugate for efficient entrapment in liposomes and prolonged residence of a drug in tissues, we synthesized a salicylic acid (SA) conjugate bound covalently with gamma-cyclodextrin (SA/gamma-CyD conjugate), a model drug/CyD conjugate, and then liposomes entrapping the conjugate (conjugate-in-liposome) were prepared by a freezing-thawing method. The chemical and physicochemical properties of the SA/gamma-CyD conjugate in solution and solid state were investigated and then the physicochemical properties of conjugate-in-liposome, in vitro cellular uptake/release and in vivo disposition of SA/gamma-CyD conjugate after intravenous administration of aqueous suspension containing conjugate-in-liposome in rats, were evaluated, comparing with those of the liposome-entrapped SA alone (SA-in-liposome) or the liposome-entrapped noncovalent SA/gamma-CyD complex (complex-in-liposome). As a result, it was found that the conjugate was amorphous powder and the release of SA from the conjugate in phosphate-buffered saline (PBS) was tolerated to chemical and enzymatic degradation. Meanwhile, the particle sizes and stability of these liposomes were almost identical, and the entrapment ratio of SA/gamma-CyD conjugate in liposomes was higher than those of SA alone and SA/gamma-CyD complex. The cellular uptake of these liposomes was almost equivalent, but the release of SA/gamma-CyD conjugate from RAW264.7 cells was markedly slower, compared with that of SA from cells following cellular uptake of the SA-in-liposome and complex-in-liposome. The disposition of SA or SA/gamma-CyD conjugate following intravenous administration of aqueous suspensions containing each liposome system in rats was comparable, but the residence time of the conjugate in tissues significantly prolonged, compared with that of the SA-in-liposome and complex-in-liposome systems. These results suggest the potential use of SA/gamma-CyD conjugate for efficient entrapment in liposomes as well as of liposomes containing SA/gamma-CyD conjugates for prolonged residence of drugs in tissues.
为了评估药物/环糊精（CyD）共轭物在脂质体中有效包封以及药物在组织中长时间留存的潜在用途，我们合成了与γ-环糊精共价结合的水杨酸（SA）共轭物（SA/γ-CyD共轭物），一种模型药物/CyD共轭物，然后通过冻融法制备了包封该共轭物的脂质体（脂质体包封共轭物）。研究了SA/γ-CyD共轭物在溶液和固态下的化学及物理化学性质，随后评估了脂质体包封共轭物的物理化学性质、体外细胞摄取/释放情况，以及在大鼠静脉注射含脂质体包封共轭物的水悬浮液后SA/γ-CyD共轭物的体内处置情况，并与单独脂质体包封的SA（SA-脂质体）或脂质体包封的非共价SA/γ-CyD复合物（复合物-脂质体）进行比较。结果发现，该共轭物为无定形粉末，在磷酸盐缓冲盐水（PBS）中SA从共轭物中的释放对化学和酶促降解具有耐受性。同时，这些脂质体的粒径和稳定性几乎相同，SA/γ-CyD共轭物在脂质体中的包封率高于单独的SA和SA/γ-CyD复合物。这些脂质体的细胞摄取情况几乎相当，但与细胞摄取SA-脂质体和复合物-脂质体后SA从细胞中的释放相比，RAW264.7细胞中SA/γ-CyD共轭物的释放明显较慢。大鼠静脉注射含各脂质体系统的水悬浮液后，SA或SA/γ-CyD共轭物的处置情况相当，但与SA-脂质体和复合物-脂质体系统相比，共轭物在组织中的留存时间显著延长。这些结果表明SA/γ-CyD共轭物在脂质体中有效包封的潜在用途，以及含SA/γ-CyD共轭物的脂质体在药物于组织中长时间留存方面的潜在用途。
