The Preparation Of Epirubicin Polybutylcyanoacrylate Magnetic Nanoparticles And Experimental Study Of Its Application In Targeting Treatment For Hepatocarcinoma

It was advanced stage when majority of primary hepatic carcinoma (PHC) was detected. 10～45% of these tumors can be removed approximately. Therefore, adjuvant chemotherapy takes an important role in the combined therapy of hepatoma.But the chemotherapeutics have severe adverse reaction all over the body when they kill cancer cells simultaneously due to non-specificity between tumor cells and normal cells.It is a difficult and hot spot how to increase the concentration of chemotherapeutics in the target organ and how to reduce that of non-target organ so as to decrease the adverse reaction in the clinical application of anticancer drugs. The targetting site-specific delivery of drugs systems will enable anticancer drugs to skip the problem.The nano-drugs delivering carriers have the capacity of delayed release of anticancer drugs and extending the duration of drug action. The targetting of drug carriers will enrich anticancer drugs in the target organ,especially those drugs with comparative noxious property and narrow therapeutic scope such as epirubicin(EPI).Consequently,they cut down the drug consumption and further avoid or relieve the adverse reaction.Epirubicin excels adriamycin in antineoplasmic activity and is lighter than the latter in toxicity,especially in heart toxicity. A variety of adriamycin delivering carriers have been designed and prepared since nanotechnology was generally applied in medical field in rencent years.The poly-alkylcyanoacrylates(PACAs) is generally accepted as one of the best polymeric drug-delivering carriers at colloidal state with favourable prospect,whose two significant features include tissue target and the capability of enhancing intracellular penetrativity of anticancer drugs.Epirubicin poly-butylcyanoacrylate nanoparticles(EPI-PBCA-NP) has been successfully prepared in National Key Laboratory of Nanobiological Technology of Ministry of Health.Poly-butylcyanoacrylate was experimentally proved to possess a series of advantages such as high stability,degradation, nontoxicity and satisfactory liver targetting. On the base of the above-mentioned studies,We plan to prepare a magnetic nanoparticles drug delivering system with Fe₃O₄ as magnetic material,with poly-butylcyanoacrylate (PBCA) as carrier and epirubicin(EPI) as targeted drug for the targeted therapy of hepatoma.Subsequently, a series of experimental studies on the magnetic nanoparticles drug delivering system will performed.The experimental study was divided into four parts as follows:1 The preparation and characterization of the epirubicin poly-butylcyanoacrylate magnetic nanoparticles(EPI-PBCA-MNPS)â‘ In this experiment,Fe3O4 nanoparticles with superparamagnetism were prepared by means of chemical precipitation,its particle diameter was 15.2±4.6nm. It can be maintained for a long time after modification of citrate sodium.â‘¡Antiphase micro emulsion interfacial polymerization was employed to prepare magnetic polymer nanoparticles(without carrying drug) with Fe₃O₄ nanoparticle as core,which possess favourable stability and uniform particle diameter 135.0±15.6nm.â‘¢With Fe₃O₄ nanoparticle as core,EPI-PBCA-MNPS(carrying drug) which has core-shell structure and satisfactory stability was prepared for next animal experiment.The mean diameter of EPI-PBCA-MNPS is 152.0±28.5nm,the average enveloping rate is 81.30±15.20% and the average carrying dosage is 14.65±2.05%.The intensity of saturation magnetization in the colloid solution of drug-carrying magnetic nanoparticles is 0.35KA·m^-1.2 A study on the targetting distribution of EPI-PBCA-MNPS in rats in vivoEPI-PBCA-MNPS have favourable magnetic response.An extraorgan magnetic field can be exerted to enrich EPI-PBCA-MNPS in the definite position of rat liver and reduce the accumulative density in the extrahepatic organs after intravenous injection of epirubicin.3 Acute toxicology experiment of EPI-PBCA-MNPSâ‘ As a well improved pharmaceutical product of EPI, EPI-PBCA- MNPS possess both of the initiative and passive targeting effects and the delayed release characteristics of nano-drugs which enable continuous and stable administration in certain local region in vivo.â‘¡It is proved that EPI-PBCA-MNPS can concentrate in the target organ liver.As a result,high concentration of topical remedy is established to obtain the maximum therapeutic effect.On the other hand,the depressed concentration of anticancer drugs in the extrahepatic organs:heart,lung, kidney and gastrointestinal tract relieves the adverse reaction and extends the dosage limit of administrating drugs safely.â‘¢EPI-PBCA-MNPS can result in abnormal serum biochemical indicators of blood routine test and hepatic and renal function,but the abnormal degree is inferior to that from EPI.4 Observation of therapeutic effect of EPI-PBCA-MNPS applied in the targeted therapy of the transplanted human hepatoma in athymic miceThe therapeutic results of the targeted therapy that EPI-PBCA-MNPS colloid solution was applied to treat the transplanted human hepatoma athymic mice model under an extraorgan magnetic field indicated that significant tumor inhibiting effect could be obtained by means of intravenous injection of EPI-PBCA-MNPS colloid solution for 3 times with 5000Gs magnetic field in the region of tumor. The inhibition ratio of tumor weight was 88.82%. The inhibition ratio of tumor volume was 96.26%. The pathological pictures confirmed the above-mentioned conclusion.