Research On The Self-amplifying Tumor-targeting Nano-drugs Based On A Conjugate Of Poly-glutamic Acid And Vascular Disrupting Agents

Efficiently targeting to tumors is a current research focus in anti-tumor drugs transport.Passive transport and active transport are two ways of anti-tumor drugs transporting in vivo.However,they all have their own drawbacks.Recently,researchers have invented a number of target sites in tumor tissue to recruit anti-tumor drugs.Their targeting ability has been dramatically increased.Based on these facts,we propose a new tumor targeting strategy that has self-amplify function.This self-amplify tumor targeting strategy is based on the vascular disrupting agents CA4,coagulation cascade mechanism and poly-L-glutamic acid-based nanoparticles.M-PEG,MAL-PEG and CA4 were grafted on the poly-L-glutamic acid(PLG).The graft copolymer was subsequently self-assembled into Nano-micelles in water.A15 peptide was incorporated on the surface of the nanoparticles by the addition reaction of the MAL group with the A15 polypeptide’s sulfhydryl.Eventually,the PLG160-g-mPEG5000-6 /MAL-PEG5000-2 / CA450 / A152(PPCA)nanoparticles were made.The mechanism of self-amplified tumor targeting is that the CA4 can be released from PPCA nanoparticles into the tumor tissue.The CA4 may selectively disrupt tumor vascular endothelial cells,and lead to bleeding and coagulation cascade.The coagulation factor FXIII is activated in the coagulation cascade.The A15 polypeptide,as a specific substrate of coagulation factor FXIII,can specifically bind to the clot.Since A15 and CA4 are all conjugated in a same nanoparticle,the more A15 reaches the tumor tissue the more CA4 comes.The explosive self-amplified tumor targeting strategy was achieved.PPCA has a significant antitumor effect.The 4T1 tumor-bearing mice were injected with PPCA and PPCA-N(without coagulation-targeted function)as control group by tail vein injection.After 26 days’ treatment,there is a significantly difference(**p<0.01)between PPCA and PPCA-N groups.The difference between PPCA groups and PBS groups(***p<0.001)is more significant.It is worth to note that the PPCA nanoparticles have no obviously toxicity to normal tissue.The amount of free CA4 which distributed in tumor tissue in PPCA groups was 7.5 times more than that in PPCA’ control groups(**p<0.01).Because this novel self-amplified targeting system has significant antitumor effect,strong targeting ability and lower side effects to normal tissue,it has a good application prospect.