Application Of Folate Functionalized Heparin And Poly(para-phenylene Ethynylene)Nanoparticles In Tumor Therapy

Recently,with the extensive application of nanotechnology in medicine,more and more nanocarriers based on polymers have made great progress in medical diagnosis and targeted therapy.However,there are still major fundamental problems that need to be understood and overcome in clinical treatment.One of them is that the complex behaviors of nanoparticles under physiological conditions are poorly understood,and detailed kinetic principles and mechanisms are still not available to guide the rational design and development of nanoparticles.Less attention has been paid to on nanoparticles composed of naturally occurring biopolymers,such as chitosan?heparin,In particular.On the other hand,for cancer patients,there is a lack of effective technical methods for early diagnosis.Thus,developing new nanoprobes and treatment to solve this problem become of great significance.In this paper,we first explored the differences between folic acid-modified nano-heparin and anti-tumor therapy with natural heparin,low molecular weight heparin and chemically modified heparin,and the mechanism of anti-tumor growth and metastasis,and confirmed the superiority of high molecular weight heparin.Then two types of nanoparticles composed of heparin biopolymers delivering the anticancer drug cisplatin(cis-diamminedichloroplatinum,DDP)were compared:a passive targeting nanoparticle consisting of heparin-DDP conjugates(HDDP),and an active targeting nanoparticle which includes folate molecules on the surface(HFDDP).Using in vivo models,we precisely determined the properties of the pharmacokinetic and antitumor efficacy of HDDP and HFDDP Nanoparticles.Finally,using nano-precipitation method,we prepared water soluble nano-fluorescent probes based on cancer cell targeting folate molecules and conjugated polymer poly(para-phenylene ethynylene)(PPEs),which can be used for in vivo imaging.The details are listed as following:(1)We demonstrated that by functionalizing natural heparin polymers(UFH)with folate(FA)molecules,the modified heparin could spontaneously self-assemble in the aqueous solution to form a nanometer particle with a size of about 20 nm.The difference between heparin-folate(HF NPs),UFH and low molecular weight heparin(LMWH)on anticoagulation in vivo and vitro were investigated,and also inhibition of tumor growth and metastasis.The mechanisms of them were investigated simply too.We proved that the modified heparin not only had better antitumor effect,and also has a better inhibitory effect on tumor metastasis.In addition,it also had a better biosafety,which provided the basis for whether the system could be applied to other natural products.(2)Targeted and non-targeted biopolymeric nanoparticles with identical hydrodynamic sizes and surface charges were quantitatively examined through ICP-MS in terms of the pharmacokinetic and biodistribution differences in detail.When adding cancer cell targeting folate molecules to the surface of the heparin nanocarriers,the amount of drug delivered to the tumor was doubled and tumor growth inhibition was significantly enhanced while systemic toxicity is further decreased.We also demonstrate the significant increases in therapeutic efficacy that active targeting has over passive in biopol-ymeric nanocarriers.The folate-targeted heparin particles offered similar therapeutic potentials compared to their synthetic long-circulating analogues,thus presenting a viable alternative for drug delivery vehicle construction using biological polymers which are easier for the body to eliminate.(3)Conductive conjugated polymers(PPEs)were prepared using chemical method,then based on these polymer,nanoprobe has been developed by nano-precipitation method with folate-modified polyethylene glycol-polycaprolactone.By grafting extended polyester side chain acting as the molecular insultors,we were able to minimize the interchain energy transfer by isolation of conjugated polymer backbones,which led to reduction of ?-? stacking.The QY increased accordingly from 0.14%up to 36%.We also demonstrated that those nanoprobes could be easily decorated with tumor targeting ligands.In addition,they showed excellent resistance to photobleaching in contrast to conventionally used fluorescent dyes(FITC),which have great potential in tumor diagnosis and treatment in the future.All these results provide a new idea and direction for design the new nanodrugs and nanoprobes based on heparin and PPEs polymer as nanocarriers.It has a great significance to further develop related nanodrugs and nanoprobes for clinical application.