Research And Development Of Mexitecan Nano-liposomes

Nanotechnology offer a promising therapeutic method in cancer treatment.By improving drug's pharmacokinetics,nanoparticulate systems increase the drug's therapeutic effects while decreasing its adverse side effects related to high dosage.Liposomes,the vesicles of phospholipid bilayer,can encapsulate both hydrophilic and lipophilic drugs and protect them from degradation.Liposomes have been extensively studied and continue to create intense interest in research since their discovery in the mid-1960 s.Since then,liposomes have been considered to be the most successful nanocarriers for drug deliver and have made their way to the market.Currently,a number of liposomal formulations are on the marker for cancer treatment and many more are in pipe line.In this regard,liposome-based combination chemotherapy(LCC)opens a novel avenue in drug delivery research and has increasingly become a significant approach in clinical cancer treatment.Among the most common classical chemotherapeutics,Camptothecin and its derivatives have good antiproliferation activity,representing a typical treatment for wide range of carcinomas including gastric cancer,colorectal cancer,ovarian cancer,leukemia and liver cancer.Camptothecin is a topoisomerase ?(Topo ?)inhibitor identified from Traditional Chinese Medicine prescription.?rinotecan are most representative drugs among the chemical modified camptothecin derivatives.The antitumor activity of irinotecan relies on its hydrolysis product in-vivo,SN-38 a camptothecin-derived active metabolite playing a direct inhibition role against topo ?,leading to suppression of both DNA replication and transcription.Because of fairly pool solubility in either water or lipid,meaning low bioavailability and adverse drug reaction,camptothecin and its derivatives have limitations in clinical use.?t is preferable to obtain a better therapeutic based on camptothecin,the idea that improving bioactivity of camptothecin by molecular editing at the same time modifying the compound into liposomal formulations can be very practical and inspirational.To develop Top ? targeted drug candidates with sophisticated liposolubility,a series of novel camptothecin derivatives were synthesized through structure-based molecular hybridization and prodrug design approach.The compounds were used as compositions in micellar emulsion preparations,and the antiproliferative efficacy of these preparations were evaluated in two cancer cell lines(A2780s and A549)in vitro.The designed molecules were afterwards optimized for better potency by modifications at the aliphatic chain,the linker and the camptothecin-yl group to reach the optimal structure 7c(TQ-B3203),an SN-38 containing compound.7c showed excellent capacity of inhibiting cell proliferation with ?C50 value at nanomolar level,and the potency was further confirmed in other human cancer cell lines(HT-29 and He PG2)superior to the positive reference ?rinotecan.7c can be a promising candidate as antitumor drug.We designed a new synthesis route based on the structure of the TQ-B3203 and studied the process development for the production of TQ-B3203 through the optimization of reaction conditions,streamline operations,improve yield and reduce the cost of synthesis.Then the process-related impurities of bulk TQ-B3203 were identified,characterized,and synthesized.Seven major impurities were revealed based on the mass spectrum(MS)and nuclear magnetic resonance(NMR)spectral data.The probable origin of the impurities from the preparation process of TQ-B3203 was also discussed.TQ-B3203 liposome(MXN-003)were prepared by methanol injection and spray drying method.Based on the results of single factor experiment,the process prescription of MXN-003 was optimized by investigate the effects of phospholipids,TQ-B3203 to phospholipid ratio,particle size of MXN-003,the employ of the organic solvent and freeze-drying protective agent.The antitumor activity and mechanism of MXN-003 were studied.Mechanism study further verified the MXN-003 as a Topo ? inhibitor is the same to camptothecin: binds to the Topo ? and DNA complex to form a ternary complex that stabilizes the structure,thereby prevents DNA re-ligation and causes DNA damage,which eventually results in cell apoptosis.The results of in vivo and in vitro antitumor activity showed that MXN-003 had excellent anti-tumor effect,and the anti-tumor activity was significantly better than the marketed drug CPT-11.Systematic study on the toxicity of MXN-003 showed that the toxicity of MXN-003 was significantly reduced compared with TQ-B3203.MXN-003 showed facial flushing,vomiting and other phenomena at medium and small amounts,and no significant changes were observed,only a small number of animals death at high doses.Bone marrow cell studies showed that MXN-003 had no significant effect on granulocytes,red blood cells,megakaryocytes,lymphocytes,and monocytes systems at low doses.However,when given at medium and high doses,there is a certain degree of damage to the bone marrow cells,and these injuries will gradually return to normal after the drug is stopped.In summary,this thesis combined camptothecin derivatives and nanoliposome drug delivery technology together,developed a novel liposome drug: MXN-003.The drug is effective to solve the defects of the similar drugs,has significant clinical advantages and excellent market prospect.