Yokoe Jun-ichi, Sakuragi Shiho, Yamamoto Kayoko, Teragaki Takuya, Ogawara Ken-ichi, Higaki Kazutaka, Katayama Naohisa, Kai Toshiya, Sato Makoto, Kimura Toshikiro
Pharmaceutical Research Division, NIPRO Corporation, Shiga, Japan.
Int J Pharm. 2008 Apr 2;353(1-2):28-34. doi: 10.1016/j.ijpharm.2007.11.008. Epub 2007 Nov 13.
To evaluate the effect of coupling of recombinant human serum albumin (rHSA) onto the surface of poly(ethylene glycol)-modified liposome (PEG liposome) on the in vivo disposition characteristics of liposomal doxorubicin (DXR), the pharmacokinetics and tissue distribution of DXR were evaluated after intravenous administration of rHSA-modified PEG (rHSA/PEG) liposomal DXR into tumor-bearing rats. rHSA/PEG liposome prepared using a hetero-bifunctional cross-linker, N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP), efficiently encapsulated DXR (over 95%). rHSA/PEG liposomal DXR showed longer blood-circulating property than PEG liposomal DXR and the hepatic and splenic clearances of rHSA/PEG liposomal DXR were significantly smaller than those of PEG liposomal DXR. It was also demonstrated that the disposition of DXR to the heart, one of the organs for DXR-related side-effects, was significantly smaller than free DXR. Furthermore, the tumor accumulation of rHSA/PEG liposomal DXR was significantly larger than that of PEG liposomal DXR. The "therapeutic index", a criterion for therapeutic outcome, for rHSA/PEG liposomal DXR was significantly higher than PEG liposomal DXR. These results clearly indicate that rHSA-conjugation onto the surface of PEG liposome would be a useful approach to increase the effectiveness and safety of PEG liposomal DXR.
为了评估重组人血清白蛋白（rHSA）偶联到聚乙二醇修饰脂质体（PEG脂质体）表面对脂质体阿霉素（DXR）体内处置特性的影响，在给荷瘤大鼠静脉注射rHSA修饰的PEG（rHSA/PEG）脂质体DXR后，评估了DXR的药代动力学和组织分布。使用异双功能交联剂N-琥珀酰亚胺基3-(2-吡啶二硫代)丙酸酯（SPDP）制备的rHSA/PEG脂质体能够高效包封DXR（超过95%）。rHSA/PEG脂质体DXR比PEG脂质体DXR具有更长的血液循环时间，并且rHSA/PEG脂质体DXR的肝脏和脾脏清除率明显低于PEG脂质体DXR。还证明了DXR在心脏（DXR相关副作用的器官之一）中的分布明显低于游离DXR。此外，rHSA/PEG脂质体DXR的肿瘤蓄积明显大于PEG脂质体DXR。作为治疗效果标准的“治疗指数”，rHSA/PEG脂质体DXR明显高于PEG脂质体DXR。这些结果清楚地表明，在PEG脂质体表面偶联rHSA将是提高PEG脂质体DXR有效性和安全性的一种有用方法。
