Department of Chemical and Materials Engineering, Chang Gung University, Kweishan, Taoyuan, Taiwan.
J Pharm Sci. 2011 Feb;100(2):655-66. doi: 10.1002/jps.22309. Epub 2010 Aug 26.
The aim of this work was to evaluate the use of thermosensitive hydrogels for intravesical cisplatin delivery into the bladder. Poly(N-isopropylacrylamide) (PNIPAM) was grafted onto hyaluronic acid (HA) to synthesize an HPN copolymer, which was further grafted with gelatin to form an HPNG copolymer. A 3% concentration of HPN and HPNG was sufficient to exert a thermosensitive response, whereas a concentration of 8% was needed for PNIPAM to form the hydrogel. The physicochemical and drug delivery properties were examined by scanning electron microscopy (SEM), the lower critical solution temperature (LCST), hydration ratio, and in vitro cisplatin release. The incorporation of HA and gelatin produced a different microstructure compared to the parent PNIPAM hydrogel. Gelatin conjugation increased the fibrous structure in the matrix. The LCSTs of PNIPAM, HPN, and HPNG were 32.3, 32.0, and 30.7°C, respectively. The copolymers showed an eightfold increase in the hydration capacity compared to PNIPAM, with no significant difference in values between HPN and HPNG. The release of cisplatin from an aqueous solution (control) was nearly complete after 8 h, compared to 85, 80, and 52% release from PNIPAM, HPN, and HPNG, respectively. In vivo evaluation of cisplatin levels in bladder tissues was performed following intravesical instillation in rats. When the dwell time was extended to 6 h, PNIPAM showed a sevenfold enhancement in the drug concentration in the bladder wall. HPNG also showed a twofold increase in the drug concentration. The administration of cisplatin by the HPN carrier did not change the drug accumulation compared to the control. Confocal laser scanning microscopic results confirmed the trend of drug absorption from various systems. A histological examination showed no adverse change in the urothelium with HPN or HPNG application. PNIPAM caused partial desquamation of umbrella cells. The thermosensitive hydrogels prepared in this study may be promising carriers for targeted drug delivery to the bladder.
本工作旨在评估温敏水凝胶在膀胱内顺铂给药中的应用。将聚（N-异丙基丙烯酰胺）（PNIPAM）接枝到透明质酸（HA）上合成 HPN 共聚物，然后将其与明胶接枝形成 HPNG 共聚物。3%浓度的 HPN 和 HPNG 足以产生热敏响应，而 8%浓度的 PNIPAM 则需要形成水凝胶。通过扫描电子显微镜（SEM）、低临界溶液温度（LCST）、水合比和体外顺铂释放来检查物理化学和药物输送性能。与亲水性 PNIPAM 水凝胶相比，HA 和明胶的掺入产生了不同的微观结构。明胶的接枝增加了基质中的纤维结构。PNIPAM、HPN 和 HPNG 的 LCST 分别为 32.3、32.0 和 30.7°C。与 PNIPAM 相比，共聚物的水合能力增加了八倍，而 HPN 和 HPNG 之间的值没有显著差异。顺铂从水溶液（对照）中的释放在 8 小时后几乎完全，而 PNIPAM、HPN 和 HPNG 分别释放 85%、80%和 52%。在大鼠膀胱内灌注后，通过体内评估膀胱组织中的顺铂水平。当驻留时间延长至 6 小时时，PNIPAM 使膀胱壁中的药物浓度增加了七倍。HPNG 也使药物浓度增加了两倍。与对照相比，HPN 载体给药并未改变药物积累。共聚焦激光扫描显微镜结果证实了从各种系统吸收药物的趋势。组织学检查显示，HPN 或 HPNG 应用不会引起尿路上皮的不良变化。PNIPAM 导致伞细胞部分脱落。本研究中制备的温敏水凝胶可能是靶向膀胱给药的有前途的载体。
