Active Targeted Delivery Of MMP2 Enzyme-sensitive Polymer Nanoparticles

Cancer has become a major killer of human.Chemotherapy is one of the main approaches of treating cancer.Currently,there are common chemotherapy drugs including paclitaxel(PTX),doxorubicin and cisplatin.Among of them,PTX is the first anticancer drug separated from natural plants.And PTX is extensively applied for the treatment of ovarian cancer,breast cancer and non-small cell lung cancer.However,PTX has many limitations such as low solubility in water,high toxicity,low bioavailability,and so on.In order to improve the treatment efficacy of chemotherapeutic drugs,the research of drug delivery system based on nanoparticles has developed.The polymeric nanoparticles for drug delivery system as one of a common nanocarriers can increase the solubility chemotherapeutic drugs in water,and achieve drugs targeted delivery and controlled release,simultaneously.In this thesis,polymer nanoparticles with enzyme-sensitive and tumor targeting were designed.In this work,PTX-loaded enzyme-sensitive nanoparticles with TPGS3350-ppl-PLGA and TPGS-Folate were fabricate.In detail,PEG3350 contained in TPGS3350 was used to stabilize the nanoparticles,prolong the circulation time of the nanoparticles in body,hide the folate of targeting ligand,and close the targeting function of the nanoparticles.When the nanoparticles reached to the MMP2 overexpressed in the tumor area,the layer of TPGS3350 was detached from the surface of nanoparticles to expose the folate on the surface of nanoparticles,thus opening the active targeting function of the nanoparticles.Consequently,the nanoparticles entered the inner of tumor cells via the folate receptor-mediated endocytosis pathway.In this work,the physical and chemical properties of nanoparticles including particle size,morphology,drug loading and drug release in vitro were investigated.Furthermore,it was confirmed by in vitro experiments that the nanoparticles show good biocompatibility and specifically kill MCF-7 cells overexpressing folate receptor.Finally,in order to investigate the anti-tumor effect of the nanoparticles,a MCF-7 subcutaneous tumor model was constructed.Compared to other groups,the growth in tumor volume treated with enzyme-responsive nanoparticles was the slow,and the body weight of the mice did not loss significantly,which indicated that the enzyme-sensitive nanoparticles designed in this work present high anti-tumor efficacy and low side effects.In summary,this work provides a new strategy for drug delivery,and explore the feasibility of applying MMP2-sensitive nanoparticles for chemotherapy in clinic.