Li XueMing, Ding Liyan, Xu Yuanlong, Wang Yonglu, Ping QiNeng
Department of Pharmaceutics, China Pharmaceutical University, Nanjing, China.
Int J Pharm. 2009 May 21;373(1-2):116-23. doi: 10.1016/j.ijpharm.2009.01.023. Epub 2009 Feb 4.
Site-specific delivery of drugs and therapeutics can significantly reduce drug toxicity and increase the therapeutic effect. Transferrin (Tf) is one suitable ligand to be conjugated to drug delivery systems to achieve site-specific targeting, due to its specific binding to transferrin receptors (TfR), highly expressed on the surfaces of tumor cells. Stealth liposomes are effective vehicles for drugs, genes and vaccines and can be easily modified with proteins, antibodies, and other appropriate ligands, resulting in attractive formulations for targeted drug delivery. In this study, we prepared doxorubicin-loaded stealth liposomes (Tf-SL-DOX) by film dispersion followed by ammonium sulphate gradient method, then conjugated Tf to the liposome surface by an amide bound between DSPE-PEG(2000)-COOH and Tf. The results of the intracellular uptake study indicated that Tf-modified SL was able to enhance the intracellular uptake of the entrapped DOX by HepG2 cells compared to SL-DOX. We studied tissue distribution and therapeutic effects of Free DOX, SL-DOX and Tf-SL-DOX in tumor-bearing mice and pharmacokinetics in rats. The pharmacokinetic behavior of Tf-SL-DOX in the plasma was closed to SL-DOX. Administration of Tf-SL-DOX to tumor-bearing mice could be used to deliver DOX effectively to the targeted site, significantly increasing DOX concentration in tumor and decreasing DOX concentration in heart and kidney. In summary, our study indicated that the Tf-coupled PEG liposomes (Tf-SL) could be as the targeted carriers to facilitate the delivery of the encapsulated anticancer drugs into tumor cells by receptor-mediated way.
药物和治疗剂的位点特异性递送可显著降低药物毒性并提高治疗效果。转铁蛋白（Tf）是一种适合与药物递送系统偶联以实现位点特异性靶向的配体，因为它能与肿瘤细胞表面高表达的转铁蛋白受体（TfR）特异性结合。隐形脂质体是药物、基因和疫苗的有效载体，并且可以很容易地用蛋白质、抗体和其他合适的配体进行修饰，从而形成有吸引力的靶向药物递送制剂。在本研究中，我们采用薄膜分散法随后用硫酸铵梯度法制备了载有阿霉素的隐形脂质体（Tf-SL-DOX），然后通过DSPE-PEG(2000)-COOH与Tf之间的酰胺键将Tf偶联到脂质体表面。细胞内摄取研究结果表明，与SL-DOX相比，Tf修饰的SL能够增强HepG2细胞对包裹的阿霉素的细胞内摄取。我们研究了游离阿霉素、SL-DOX和Tf-SL-DOX在荷瘤小鼠中的组织分布和治疗效果以及在大鼠中的药代动力学。Tf-SL-DOX在血浆中的药代动力学行为与SL-DOX相近。给荷瘤小鼠施用Tf-SL-DOX可有效地将阿霉素递送至靶向部位，显著提高肿瘤中阿霉素的浓度并降低心脏和肾脏中阿霉素的浓度。总之，我们的研究表明，Tf偶联的聚乙二醇脂质体（Tf-SL）可作为靶向载体，通过受体介导的方式促进包裹的抗癌药物递送至肿瘤细胞。
