Synthesis and anti-cancer evaluation of folic acid-peptide- paclitaxel conjugates for addressing drug resistance

Authors: Dai, Yuxuan; Cai, Xingguang; Bi, Xinzhou; Liu, Chunxia; Yue, Na; Zhu, Ying; Zhou, Jiaqi; Fu, Mian; Huang, Wenlong; Qian, Hai; European Journal of Medicinal Chemistry; (2019); 10.1016/j.ejmech.2019.03.031

The drug resistance and the poor water solubility are major limitations of paclitaxel (PTX) of based chemotherapy. To conquer the two problems, targeting folate (FA) receptor PTX-lytic peptides conjugates were synthesized and evaluated. Compared with PTX, FA-P3-PTX and FA-P7-PTX displayed significantly enhanced cell toxicity in many cancer cells, particularly drug resistant cancer cells MCF-7/PTX. FA-P7-PTX possessed stronger effect on cell toxicity (IC50 = 2.92 ± 0.2 μM), membrane disrupting activity and pro-apoptosis in MCF-7/PTX cells than FA-P3-PTX. Further investigation displayed that the anti-cancer mechanisms of FA-P3-PTX and FA-P7-PTX might be a mitochondrial impairment and caspase-3-dependent apoptotic cell death. Furthermore, the in vivo antitumor efficacy study confirmed that FA-P7-PTX performed more stronger potency in inhibition of tumors growth than PTX. The study demonstrated that conjugate FA-P7-PTX with superior properties for antineoplastic activity, which makes it a promising potential candidate for drug-resistant cancer therapy.