Design,Synthesis And Tumor Targeted Research Of Acid Sensitivity CPPs:Methyl-TH,Ethyl-TH

In the process of cancer treatment,radiotherapy and chemotherapy are the two most common methods.Due to poor traditional cell selective and strong side effects of the antitumor drugs,brought great pain to cancer patients.The frequent use of traditional anti-tumor drugs,caused the multi-drug resistance,resulting in a large number of the chemotherapy drug efficacy to reduce or even loss,which serious threat to human life and health.Therefore it is critical to development new tumor target anti-tumor drugs.In this context,a special kind of peptide caught the attention of the scholars,called cell-penetrating peptide(CPPs).CPPs can penetrate the cell membrane into cytoplasm,of course,more important is that CPPs serving as vectors,which can successfully intracellular transport cargoes such as siRNA,nucleic acids,small molecule therapeutic agents,proteins and MRI contrast agents,and show the corresponding pharmacological activity.In our previous research,Histidine can be protonated into positive charge under the acidic tumor microenvironment and remain slightly negatively charged at normal physiological condition.We designed and synthesized a new cell-penetrating peptide TH(AGYLLGHINLHHLAHL(Aib)HHIL-NH2),which replaced all the lysine in peptide TK(AGYLLGKINLKKLAKL(Aib)LLIL-NH2)with histidines.In order to further verify the pH-sensitive activity of TH,We choose disulfide bridge attach the antineoplastic drugs podophyllotoxin(PPT)to TH,and finally get the analogue TH-PPT,the results showed that the TH-PPT presents obvious pH-responsive antitumor activity.In order to further improve the pH-sensitivity of the TH,we designed and synthesized another two new cell-penetrating peptide Methyl-TH and Ethyl-TH,in which introduce Methyl and Ethyl into the imidazole group of histidine in the sequence of TH.Their efficiency of cell uptake at pH6.0,pH6.5,pH7.4 and toxicity in vitro were evaluated.The results demonstrated that the analogues of TH shown lower toxicity and Ethyl-TH own a better pH-responsive.Meanwhile,the Ethyl-TH-CPT could preferentially enter cancer cells in acidic environment.