Tsukioka Yoshihisa, Matsumura Yasuhiro, Hamaguchi Tetsuya, Koike Hiroyo, Moriyasu Fuminori, Kakizoe Tadao
Department of Medicine,National Cancer Center, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Jpn J Cancer Res. 2002 Oct;93(10):1145-53. doi: 10.1111/j.1349-7006.2002.tb01217.x.
The stability and biological behavior of an in vitro system of doxorubicin (DXR) entrapped in NK911, polymer micelles, was examined and compared with those of DXR entrapped in Doxil, polyethylene-glycol-conjugated liposomes. The fluorescence of DXR inside micelles or liposomes in an aqueous solution is known to be strongly quenched by the outer shells of the micellar or liposomal formation. Thus, by measuring the fluorescence intensity of DXR released from NK911 or Doxil, we could determine the stability of the micellar or liposomal DXR formation. Furthermore, NK911 was found to be less stable than Doxil in saline solution. In drug distribution experiments using an in vitro solid tumor model, when spheroids formed from two human colonic cancer lines, HT-29 and WiDr, and a human stomach cancer line, MKN28, were exposed to NK911, DXR was distributed throughout the spheroids, including their center. On the other hand, when the spheroids were exposed to Doxil, DXR was distributed only to the surface of the spheroids. It has been suggested that Doxil can deliver DXR to a solid tumor more efficiently than NK911 via the EPR (enhanced permeability and retention) effect, because Doxil may be more stable in plasma than NK911. On the other hand, DXR packed in NK911 may be distributed by diffusion to cancer cells distant from the tumor vessel, because NK911 can leak out of the tumor vessel and may be able to release free DXR more easily than Doxil. It has been suggested that drug carrier systems such as liposomes and micelles should be selected appropriately bearing in mind the characteristics of the tumor vasculature and the tumor interstitium.
研究了包裹在聚合物胶束NK911中的阿霉素（DXR）体外系统的稳定性和生物学行为，并与包裹在聚乙二醇共轭脂质体Doxil中的DXR进行了比较。已知水溶液中胶束或脂质体内DXR的荧光会被胶束或脂质体形成的外壳强烈淬灭。因此，通过测量从NK911或Doxil释放的DXR的荧光强度，我们可以确定胶束或脂质体DXR形成的稳定性。此外，发现NK911在盐溶液中的稳定性低于Doxil。在使用体外实体瘤模型的药物分布实验中，当由两种人结肠癌细胞系HT - 29和WiDr以及一种人胃癌细胞系MKN28形成的球体暴露于NK911时，DXR分布在整个球体中，包括其中心。另一方面，当球体暴露于Doxil时，DXR仅分布在球体表面。有人提出，由于Doxil在血浆中可能比NK911更稳定，通过EPR（增强的通透性和滞留）效应，Doxil可以比NK911更有效地将DXR递送至实体瘤。另一方面，包裹在NK911中的DXR可能通过扩散分布到远离肿瘤血管的癌细胞，因为NK911可以从肿瘤血管中漏出，并且可能比Doxil更容易释放游离的DXR。有人提出，应根据肿瘤脉管系统和肿瘤间质的特征适当选择脂质体和胶束等药物载体系统。
