Research On Novel MOFs-derived Magnetic Porous Carbon Served As Drug Carriers

The pioneers of scientific researches have paid a lot of attention to carbon nano-materials since they were discovered.Owing to their long residency in vivo,high drug-loading rate,high cellular intake rate,good biocompatibility,carbon nano-materials showed great potential in drug delivery.However,due to their chemical interness,carbon nano-materials also have some drawbacks such as instable drug loading via π-π stacking and difficulties in chemical modifications.Metal Organic Frameworks(MOFs)is one of the most developed inorganic porous materials,which not only has porous structure,but also CO2-/Fe3+ coordination structure.If we use MOFs as template to prepare carbon nano-materials,the synthesized carbon nano-materials might inharit the organized porous structure of MOFs and might form the magnetic particles by interactions between Fe3+ and carboxyl.MOF-derived carbon nano-materials might have porous structure and stable magnetism,which enables them to have high drug loading capacity,sustained release effect,magnetic targeting,magnetothermal effect,magnetic controlled release effect,etc.These properties might make them good for drug delivery systems.MIL-100 is one of the most famous MOFs,which is coordinated by iron ions and trimesic acids.In this study,we used MIL-100 as template to prepare a novel magnetic MOF-derived porous carbons(MMPCs)by high temperature burning method.We used MMPCs to load anti-tumor drug paclitaxel(PTX)to form MMPC-PTX drug delivery system,which could achieve magnetic targeting,magnetic controlled release,thermal therapy and chemical therapy simultaneously.The in vitro and in vivo anti-tumor efficiency of MMPC-PTX were investigated.The main subject of this thesis is as follows:To determine the potential of MMPCs to be used in drug delivery system,we designed series of experiments to measure their possible high drug loading capacity,sustained release effect and magneticsm.Results showed that the size of MMPCs was between 50 – 100 nm,zeta potential was-15.7 ± 1.3 mV.Drug loading experiments showed that when mass ratio was 1:3(MMPCs:PTX),the drug drug loading rate ofMMPCs was 114.17 ± 32.26 %,while the drug loading rate of template MIL-100 was only 52.95 ± 7.02%.This indicated that MMPCs had high drug loading capacity than MIL-100.Drug release experiment showed that MMPCs could slowly release drugs in 48 hours.Cellular uptake experiments showed that after 48 h,the uptake rate was still 20.70 ± 5.64 %,which indicated that MMPCs could slowly release fluorescence molecules in cells.In vivo drug release experiment showed that six days after administration of MMPC-PTX,the blood concentration of PTX was1.83 ± 0.45 mg/L.This indicated that MMPC-PTX had sustained release effect in vivo.Magnetism measurement showed that MMPCs had stable superparamagetism.It was also proved that MMPCs had good magnetic targeting effect and magnetothermal effect in vitro and in vivo.After alternative magnetic field(AMF)stimulation,the drug release was accelerated – after 24 h,cellular uptake rate rose by 19.80 % after AMF stimulation.In vivo drug release experiments showed that after AMF stimulation,the plasma concentration of PTX increased by 8.17 mg/L.This indicated that AMF stimulation could accelerate the drug release.Afterwards,we mesuared MMPCs’ cytotoxicity and cellular uptake rate.MMPCs showed no severe cytotoxicity in human breast cancer cell line MCF-7,human esophageal carcinoma cell line EC-109,human gastric cancer cell line MGC-803 and human liver cancer cell line Hep G2.They also showed limited influence to cellular apoptosis and cell cycle.Cellular experiments also demonstrated that MMPCs could be taken in by MCF-7 cells,and cellular uptake rate could achieve93.40 ± 6.33 % after 4-hour incubation.This indicated that MMPCs had low cytotoxicity and high cellular uptake rate.After investigating the potential of MMPCs to be used in drug delivery system.We used paclitaxel(PTX)as model drug to form the MMPC-PTX drug delivery system.The anti-tumor efficiency of MMPC-PTX was detected in vitro and in vivo.Results showed that in cellular level,MMPC-PTX had relatively high proliferation inhibition rate,and could induce cellular apoptosis and inhibit cell division by G2/M arrest.After AMF stimulation,the cellular proliferation inhibition rate and apoptosis-inducing ability was enhanced,while cell cycle change was not influenced.In vivo,the tumor inhibition rate of MMPC-PTX could arrived 79.51 % after three administrations.The biocompatibility of MMPC-PTX was investigated by monitoring the behavior of dosed mice,testing blood and liver index,calculating organ coefficient and analyzing HE staining sections of each organs.Results showed that the side effect of PTX like myelosuppression,toxicity of respiratory system and liver could be reduced.After AMF stimulation,the anti-tumor efficiency of MMPC-PTX was enhanced,and the tumor inhibition rate of MMPC-PTX arrived 88.55 %.What’s more,after magnetic targeting,the myelosuppression,liver and lung toxicity was also reduced.This study proved that MMPCs had high drug loading capacity,sustained release effect,magnetic targeting effect,magnetothermal effect,magnetic controlled release effect,etc.The synthesized MMPC-PTX drug delivery system had good anti-tumor efficiency in vitro and in vivo.This study successfully prepared novel carbon nano-materials using MOFs as template.In further study,the morphorlogy and pore size of MOFs could be altered by changing organic ligands and metal ions.Multiple kinds of MOFs could be used to prepare carbon nano-materials with different structure and functions.This study explored a new way to prepare drug carriers for targeting therapy.