Design Of Multi-targeting "Laso-like" Self-assembling Peptide And It’s Anticancer Research

Cancer is one of the main threats to human life.For many years,lots of therapeutic strategy and drugs have been invented and developed to eliminate these threats.However,commonly used anti-tumor drugs have problems such as poor targeting,toxicity,and drug resistance,new therapies and drugs are urgently needed to be developed.Peptide drugs have great potential in the field of cancer targeted therapy because of their diverse structure,rich functions,low toxicity and high biocompatibility.Anti-tumor lytic peptides can target the most conserved part of cells-cell membrane.It is the least susceptible to induce drug resistance.Many naturally occurring broad-spectrum antibacterial peptides also have anti-tumor ability,but these anti-tumor peptides are generally not targeted,and common peptide drugs are generally poorly stable and have a short half-life in vivo which limit their application.Herein,we designed a "lasso-like" peptide LASAP(CRGDKGPDCGKAFRRFLGALFKALSHLL,1-9 disulfide bond)with multi-targeting and self-assembling abilities.LASAP could self-assemble into homogeneous nanoparticles(～30nm),exhibiting improved stability in serum and protease solutions.Major secondary structure of the self-assembly is α-helix.In vitro,LASAP self-assembly exhibited cytotoxicity and pH sensitivity on prostate cancer cell line(22Rvl)and cervical cancer cell line(Hela).The nanoparticles could response to acidic pH and human glandular kallikrein-2(hK-2),leading to enhanced cytotoxicity.LASAP showed specific binding to integrin avp3 and accumulation at the tumor site,because iRGD sequence has the ability to target αvβ-integrin.Orthotopic prostate tumor mouse model was established using prostate cancer cell line 22Rvl to test the in vivo efficacy of LASAP.After two weeks of treatment by LASAP nanoparticles(i.p.31.25mg/kg),the tumor growth was significantly inhibited(P<0.05),showing a comparable effect to docetaxel(DTX),but with much lower toxicity.