The Research Of Biodegradable Polymer Platinum Drug Conjugates On The Orthotopic Liver Tumor Targeted Therapy

Known as the "cancer of the King" of liver cancer, has been the major threat tohuman health. In worldwide the morbidity and mortality is very high and increasesyear by year. The average survival time is only3-9months.At present, the maintreatment for liver cancer includes surgical resection, liver transplantation,interventional, radiofrequency ablation and chemotherapy, during whichchemotherapy is the main method. However, according to the clinical treatment,higher chemotherapy drug dose has severe side-effects and results in the great pain,poor quality of life and limited prolonged survival time for patients. The key toimproving the effectiveness of chemotherapy drugs lies in the effective targetingwhile reducing the side-effects of drugs. The shortcomings associated withconventional anticancer drugs including lack of selectivity, rapid clearance,insolubility under aqueous condition result in poor therapeutic effect. Therefore, thedevelopment of high efficiency and low toxicity of new anticancer drugs has been thefocus of bio-pharmaceutical industry at home and abroad.Recently, polymer drug conjugate provides a technical means to overcome theshortcomings of chemotherapy drug."Polymer conjugate drugs"refers to: platinumdrugs through covalent bond connection ways of combining into the polymer carrier,made certain pharmaceutical dosage form, by oral or intravenous injection, to transfer"Polymer conjugate drugs" in the patient’s body, arriving at a particular tissue ororgans, the small molecule platinum drugs under physiological conditions frompolymer carrier over from down, the thus play a role of treatment of tumor cells.Inrecent years, the development of nano-biomedical science has a profound impact onthe biological medicine. Nano micelles because of the comparable size with biological molecules and easy transport in the body environment have been widely investigated.The hydrophobic core of micelle self-assembled from amphiphilic copolymer canprotect the polymer conjugate drugs effectively. In addition, the conjugate drug willnot escape from the micelles by diffusion, thereby avoiding the sudden release ofdrugs and improving the bioavailability of drugs and reducing the side effects ofdrugs.Usage in clinic, platinum drugs, annual statistics about all of the anti-cancer drugusage, metal platinum anticancer drug usage is about more than half of all cancerdrugs.With carboplatin, oxaliplatin into at the end of last century were developed,they belong to a new type of bivalent platinum anticancer drug varieties, they arecompared with the first generation of platinum drugs, effectively reduce the sideeffect on organism, in clinical antitumor therapy for good clinical curative effect.Tetravalent platinum complexes (referred to as platinum(IV)) are another kind ofplatinum drugs. Compared with platinum(II), the two more axial ligands inplatinum(IV) results in the formation of octahedral structure, which constrains thereactivity of the platinum(IV) complex and significantly reduces the toxicity ofplatinum(IV). Therefore, platinum complexes(IV) have opened up a new way todevelop a highly efficient and less toxic platinum drugs. The platinum(IV) complexesare reduced into platinum(II) species quickly when platinum(IV) drugs is deliveredinto the tumor region or the tumor cell.This topic “Polymer conjugate drugs”in the past work, on the basis of thecombination of small molecule metals platinum drugs structure-activity relationshipbetween small molecules and platinum drugs polymer and the drug combination ofbonding technology, from the viewpoint of the design synthesis of platinum (IV) drugs can fall as well as the biological function of amphiphilic block copolymer withplatinum (IV) bonding material, achieve the effective protection of platinum (IV) andtargeted delivery, and the polymer platinum drugs platinum (IV) and polymer carrierconducted a series of characterization.In this paper, in situ liver cancer tumors in micemodel was established to directly grown in kunming mouse liver cancer H22cellswithin the liver. This cancer model is highly clinically relevant and can better simulatethe biological characteristics of human liver cancer. Moreover, the model is easy tooperate and can be constructed successfully. Therefore, the orthotopic liver tumormodel has great value and will become important in human hepatocellular carcinomaanimal models in the future.This paper made the following work:(1)Artificial synthesis of small molecules in the laboratory of platinum drugs,including oxaliplatin (II) into, oxaliplatin (IV)into, scientific research institutions inthe country through the means such as ir,1HNMR, ms and confirmed their molecularstructure, exact credible;(2)Biodegradable polymer was synthesized successfully in the laboratory,scientific research institutions in the country by ir,1HNMR, ms and confirmed itsmolecular chemical structure;(3)Oxaliplatin(IV) into small molecule drugs through covalent bond connectionto the polymer carrier, and assembled into nano drug.Through determined by MTTtest and animal experiments confirmed that the polymer-platinum (IV) drugs thansmall molecule oxaliplatin into more efficient;(4)H22hepatoma cells were injected directly into the liver by laparotomy andorthotopic mouse tumor model was successfully established, which provided morereliable experimental results. (5)Implements the oxaliplatin (IV)drugs into nanometer transport of smallmolecules, effectively solve the oxaliplatin(II)drugs into high efficient drug problems,which is the bottleneck problem of oxaliplatin into clinical application.