To ameliorate the deficiencies (e.g. solubility, membrane permeability and non-selective cytotoxicity) of paclitaxel (PTX), we synthesized a “smart” PDC (peptide-drug conjugate), by linking PTX with a multifunctional peptide consisting of a tumor targeting peptide (TTP) and a cell penetrating peptide (CPP), to construct the TTP-CPP-PTX conjugate, LTP-1. LTP-1 could intelligently deliver PTX into LHRH receptor-overexpressed MCF-7 cells, showing 2 times higher cellular uptake than PTX, and enhanced cytotoxicity with IC₅₀ of 3.8 nM (vs 6.6 nM for PTX). LTP-1 exhibited less cytotoxicity to normal cells and the ability to overcome PTX-resistance. Furthermore, LTP-1 had higher in vivo antitumor efficacy than PTX (TGI of 83.4% and 65.7% for LTP-1 and PTX, respectively, at 12 mmol/kg) without apparent toxicities. In summary, we proposed and testified the concept of constructing a novel PDC molecule, which can potentially conquer the drawbacks of PTX. LTP-1 represents a new class of antitumor PDC deserving further investigation.

为了改善紫杉醇（PTX）的缺陷（例如溶解度，膜通透性和非选择性细胞毒性），我们通过将PTX与由肿瘤靶向肽组成的多功能肽连接起来，合成了“智能” PDC（肽-药物共轭物）（ TTP）和细胞穿透肽（CPP），以构建TTP-CPP-PTX缀合物LTP-1。LTP-1可以智能地将PTX递送到过表达LHRH受体的MCF-7细胞中，显示出比PTX高2倍的细胞摄取，并增强了细胞毒性，IC ₅₀为3.8 nM（PTX为6.6 nM）。LTP-1对正常细胞的毒性较小，并且具有克服PTX耐药性的能力。此外，LTP-1具有更高的体内比PTX的抗肿瘤功效（LTP-1和PTX的TGI分别为83.4％和65.7％，在12 mmol / kg时）无明显毒性。总而言之，我们提出并验证了构建新型PDC分子的概念，该分子可以潜在地克服PTX的弊端。LTP-1代表了一类新的抗肿瘤PDC，值得进一步研究。