口服聚乙二醇修饰固体脂质纳米粒的组织分布及抗肿瘤药效学研究

目的 研究口服固体脂质纳米粒(solid lipid nanoparticle，SLN)和经聚乙二醇(polyethylene glycol，PEG)修饰后的SLN(pSLN)在小鼠体内的组织分布及药效。方法 采用水性溶剂扩散法制备SLN，用聚乙二醇单硬脂酸酯(PEG2000-SA)修饰以提供亲水基团；测定其粒径、Zeta电位、表面元素、接触角和稳定性；以DiR为荧光标记物，测定SLN及pSLN制剂经口服给药后的体内组织分布；以阿霉素为模型药物，考察口服脂质纳米给药系统的体内抗肿瘤活性及安全性。结果 SLN经PEG修饰后，得到的pSLN制剂粒径降低，Zeta电位约为-20 mV，表面亲水性及体内稳定性增加；经口服给药后，pSLN在肿瘤组织有聚集，且经PEG修饰后的纳米粒在组织中的滞留时间可显著延长；在荷瘤裸鼠模型动物上的药效学结果显示，PEG修饰口服脂质纳米给药系统在改善药效的同时，降低药物的不良反应，提高给药系统的安全性。结论 PEG修饰改善了口服纳米给药系统的生物分布及药效，提高了给药系统的安全性。

Tissue-distribution and Anti-tumor Pharmacodynamics of PEGylated Solid Lipid Nanoparticles after Oral Administration

OBJECTIVE To investigate the tissues distribution and anti-tumor pharmacodynamics of monostearin solid lipid nanoparticles (SLN) and SLN modified by PEG2000-SA (pSLN) in vivo of mice. METHODS The SLN was prepared by aqueous solvent diffusion method, subsequently modified with PEG2000-SA as hydrophilic groups. The particle diameters, Zeta potentials, surface element, contact angle and stability of SLN and pSLN were determined. Tissues distributions of SLN and pSLN preparations in vivo of rats after oral administration were determined and the determining results were calculated with DiR as fluorescent marker. The in vivo antitumor efficacy and safety of the DOX-loaded nanoparticles was evaluated using BEL-7402 bearing mice model after oral administration. RESULTS The size of pSLN was smaller than that of SLN after modified by PEG. The Zeta potential of pSLN was about -20 mV and the surface hydrophilicity was improved after PEGylation of SLN. The pSLN accumulated in the tumor tissues and liver after oral administration, and the residence time in the tissue of nanoparticles was significantly prolonged after modified by PEG-SA. Furthermore, in vivo studies indicated that pSLN as a nanocarrier for the oral drug delivery system conducted well in maintaining therapeutic effects and inhibiting the growth of the solid tumor while reducing the toxicity against animal body. CONCLUSION Oral delivery of SLN can improve bio-distribution in vivo after modification with PEG-SA while reducing toxicity to normal tissue.