In this study, six N‐1, N‐2, or N‐11 derivatives of TD‐34 (a cationic cyclic cell‐penetrating peptide [CPP], ACSSKKSKHCG) were designed and synthesized including both linear peptides and cyclic peptides, such as DL‐1 (KWSSKKSKHCG), DLCC‐1 (cyclopeptide, KWSSKKSKHCG), DL‐2 (KWSSKKSKHCG‐NH₂), DLCC‐2 (cyclopeptide, KWSSKKSKHCG‐NH₂), DL‐3 (RWSSKKSKHCG), and DLCC‐3 (cyclopeptide, RWSSKKSKHCG). The cyclic peptides were synthesized by disulfide bound linkages formed by N‐2 and N‐10 cysteine. In vitro penetration experiment was conducted to investigate the transdermal enhancement ability of these derivatives, using triptolide (TP) as model drug. The results display that at the presence of DLCC‐2, the accumulative penetration amount of TP increased 1.71‐fold (P < .05) within 12 hours, displaying better transdermal enhancing ability than TD‐34. Meanwhile, DL‐3 and DLCC‐3 slightly decreased the transdermal delivery of TP, and the presence of DL‐1 and DLCC‐1 shows no obvious effect. In order to clarify the factors on the transdermal ability of peptides, the solubility of TP in phosphate buffer saline (PBS) at the presence of different peptides and the mechanism of transdermal delivery of CPPs was investigated. The result shows that most of these peptides have no significant effect on the solubility of TP except DLCC‐3 (the solubility of TP slightly increased). And in order to investigate transdermal absorption route of DLCC‐2, polyarginine linked to rhodamine b (Rh b) derivative is used. The result proved that the transdermal route of polyarginine is via hair follicle, which may change the transdermal route of its cargo molecule (TP). Our group previously proved that polyarginine and TD‐34 have similar transdermal enhancing mechanism (changing the transdermal route of their cargo molecule); it is reasonably speculated that the transdermal route of DLCC‐2 is the same as polyarginine and then changes the transdermal absorption route of TP. Furthermore, such results have laid a solid foundation for further investigation of CPPs and paved a way for both designing and synthesizing of new drug delivery system for therapy molecules.

中文翻译：

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基于TD-34的新型细胞穿透肽的合成，表征和评估。

在这项研究中，设计并合成了TD-34的六种N-1，N-2或N-11衍生物（阳离子循环细胞穿透肽[CPP]，ACSSKKSKHCG），包括线性肽和环状肽，例如DL-1（KWSSKKSKHCG），DLCC-1（环肽，KWSSKKSKHCG），DL-2（KWSSKKSKHCG-NH ₂），DLCC-2（环肽，KWSSKKSKHCG-NH ₂），DL-3（RWSSKKSKHCG）和DLCC-3（环肽（RWSSKKSKHCG）。环状肽是由N-2和N-10半胱氨酸形成的二硫键合成的。以雷公藤内酯（TP）为模型药物，进行了体外渗透实验以研究这些衍生物的透皮增强能力。结果显示，在DLCC-2存在下，TP的累积渗透量增加了1.71-倍（P<.05）在12小时内显示出比TD-34更好的透皮增强能力。同时，DL-3和DLCC-3略微降低了TP的透皮递送，并且DL-1和DLCC-1的存在没有明显的作用。为了阐明肽的透皮能力的因素，研究了在不同肽存在下TP在磷酸盐缓冲盐水（PBS）中的溶解度以及CPP的透皮递送机制。结果表明，除DLCC-3（TP的溶解度略有增加）外，这些肽中的大多数对TP的溶解度没有显着影响。为了研究DLCC-2的透皮吸收途径，使用了与罗丹明b（Rh b）衍生物连接的聚精氨酸。结果证明聚精氨酸的透皮途径是通过毛囊，这可能会改变其货物分子（TP）的透皮途径。我们的研究小组先前证明，聚精氨酸和TD-34具有类似的透皮增强机制（改变其货物分子的透皮途径）。有理由推测，DLCC-2的透皮途径与聚精氨酸相同，从而改变了TP的透皮吸收途径。此外，这些结果为进一步研究CPP奠定了坚实的基础，并为设计和合成用于治疗分子的新药物递送系统铺平了道路。有理由推测，DLCC-2的透皮途径与聚精氨酸相同，从而改变了TP的透皮吸收途径。此外，这些结果为进一步研究CPP奠定了坚实的基础，并为设计和合成用于治疗分子的新药物递送系统铺平了道路。有理由推测，DLCC-2的透皮途径与聚精氨酸相同，从而改变了TP的透皮吸收途径。此外，这些结果为进一步研究CPP奠定了坚实的基础，并为设计和合成用于治疗分子的新药物递送系统铺平了道路。