Human serum albumin (HSA) is a superior carrier for delivering extracellular drugs. However, the development of a cell-penetrating HSA remains a great challenge due to its low membrane permeability. We report herein on the design of a series of palmitoyl-poly-arginine peptides (CPPs) and an evaluation of their cell-penetrating effects after forming a complex with HSA for use in intracellular drug delivery. The palmitoyl CPPs forms a stable complex with HSA by anchoring itself to the high affinity palmitate binding sites of HSA. Among the CPPs evaluated, a cyclic polypeptide composed of D-dodecaarginines, palmitoyl-cyclic-(D-Arg)₁₂ was the most effective for facilitating the cellular uptake of HSA by HeLa cells. Such a superior cell-penetrating capability is primarily mediated by macropinocytosis. The effect of the CPP on pharmacological activity was examined using three drugs loaded in HSA via three different methods: a) an HSA-paclitaxel complex, b) an HSA-doxorubicin covalent conjugate and c) an HSA-thioredoxin fusion protein. The results showed that cell-penetrating efficiency was increased with a corresponding and significant enhancement in pharmacological activity. In conclusion, palmitoyl-cyclic-(D-Arg)₁₂/HSA is a versatile cell-penetrating drug delivery system with great potential for use as a nano-carrier for a wide diversity of pharmaceutical applications.

人血清白蛋白（HSA）是传递细胞外药物的优良载体。然而，由于其低的膜渗透性，细胞渗透性HSA的开发仍然是巨大的挑战。我们在此报告一系列棕榈酰-聚精氨酸肽（CPPs）的设计以及与HSA形成复合物用于细胞内药物递送后其细胞穿透作用的评估。棕榈酰CPP通过将自身锚定在HSA的高亲和力棕榈酸酯结合位点上而与HSA形成稳定的复合物。在所评估的CPP中，由D-十二烷基精氨酸，棕榈酰基-环-（D -Arg）₁₂组成的环状多肽对促进HeLa细胞对HSA的细胞吸收最有效。这种优异的细胞穿透能力主要是由巨胞饮作用介导的。通过三种不同的方法，使用三种装载在HSA中的药物检查了CPP对药理活性的影响：a）HSA-紫杉醇复合物，b）HSA-阿霉素共价结合物，以及c）HSA-硫氧还蛋白融合蛋白。结果表明，细胞穿透效率增加，并且药理活性相应且显着增强。总之，棕榈酰基-环-（D -Arg）₁₂ / HSA是一种多功能的细胞穿透药物递送系统，具有作为纳米载体用于多种药物应用的巨大潜力。