Construction Of Iron-based Magnetic Starch Drug Delivery Systems And Their Drug Loading/release Mechanisms

Cancer is one of the significant sources of death worldwide,and its incidence is increasing rapidly.In recent years,researchers have attempted to explore novel and effective drug delivery systems for cancer therapy.The optimal magnetic drug delivery systems are usually based on magnetic nanoparticles(MNPs)including Fe3O4,Mg Fe2O4,etc.,because of their superior biocompatibility,diverse loading capacity,controlled drug release performance and thermal effect in alternating magnetic fields.However,individual MNPs have drawbacks such as the tendency to aggregate,poor stability,and low dispersion in solutions.Functionalized modification of MNPs with starch or its derivatives can improve these undesirable properties and construct magnetic starch-based drug delivery systems(MSDDSs)with multiple responses.MSSDSs can combine the excellent properties of both MNPs and starch,which not only can provide local heating of the tumor site under magnetic field,but also may achieve controlled release of the drug due to the unique functional groups of starch.In this work,two novel MSDDSs were constructed by co-precipitation and cross-linking methods using MNPs and cassava starch(CS)as substrates and doxorubicin(DOX)as a model drug to explore their structure and property change patterns.Theoretical models were used to reveal their drug loading and release mechanisms,and cellular experiments were conducted to evaluate their biological effects in vitro,which could play a deductive role in exploring the biomedical applications of MSDDSs.The main work and findings were as follows:(1)CS@Fe3O4 NPs were synthesized in situ based on co-precipitation method and the influence of CS addition on the structure and properties of Fe3O4 NPs were investigated.The results showed that the CS@Fe3O4 NPs were cubic spinel structures with small nano-size and desirable superparamagnetic properties.When the concentration of CS solution was 1%,the characteristic CS structure started to appear in the structure of CS@Fe3O4 NPs.The thermal stability and maximum saturation magnetization(Ms)of CS@Fe3O4 NPs decreased with the increase of nonmagnetic material(CS).No covalent bonds were formed between CS and Fe3O4 NPs,but a possible hydrogen bonding interaction existed.(2)The carboxymethyl cassava starch(CMCS)products with three different degrees of substitution(DS),low,medium and high,were successfully prepared by first modifying the CS with carboxymethylation using reaction time as a single variable.Subsequently,novel CMCS@Fe3O4 NPs with cubic spinel structure,smaller particle size and superparamagnetic properties were synthesized in situ by a one-pot co-precipitation method using the obtained CMCS as the coating materials.It was found that the maximum thermal degradation temperature(Tmax)of all CMCS@Fe3O4 NPs was higher than that of the corresponding CMCS sample,which was probably due to the presence of hydrogen bonding interactions between CMCS and Fe3O4 NPs,leading to the increased thermal stability.The higher DS value of CMCS functionalized with Fe3O4 NPs decreased their thermal stability.(3)The batch adsorption experiments indicated that the CMCS@Fe3O4 NPs obtained by functionalizing Fe3O4 NPs with a high DS value of CMCS exhibited a better capacity for DOX adsorption.The adsorption rate could be as high as 85.46% at the conditions of 30 ℃,the p H value of 7.0,CMCS@Fe3O4 NPs concentration of 20 mg/m L and DOX concentration of 50 mg/m L.The adsorption kinetics,isotherms and thermodynamic results revealed that the DOX adsorption process of CMCS@Fe3O4 NPs followed the Langmuir model,a pseudo-secondary kinetic model with intra-particle diffusion,and the adsorption process was exothermic and could proceed spontaneously.The adsorption process was dominated by both chemisorption and physical adsorption,and the interactions between DOX and CMCS@Fe3O4 NPs mainly included electrostatic interactions,hydrogen bonding interactions,n-π interactions,etc.(4)Mg Fe2O4 NPs with single-phase structure were successfully prepared based on the sol-gel method.As the calcination temperature rose,the elemental Fe content in Mg Fe2O4 NPs increased.On the contrary,the actual Mg content was relatively decreased,the pyramidal structure in the crystals of Mg Fe2O4 NPs was more integrated,and the magnetic properties were increased.The novel intelligent CMCS-SA@Mg Fe2O4@DOX gel beads were successfully prepared by crosslinking different ratios of CMCS with sodium alginate(SA),Mg Fe2O4 NPs and DOX in a co-blended manner.With increasing the mass ratio of CMCS to SA,the drug loading of the gel beads could be elevated to 12.58 ± 0.39 %.Furthermore,the swelling rate of drug-loaded gel beads in p H 6.8 and 7.8 media were significantly higher than that at p H 1.8.(5)The in vitro drug release behavior of CMCSSA@Mg Fe2O4@DOX gel beads was systematically evaluated by simulating different human gastrointestinal environments and adding an external magnetic field(EMF).In neutral or slightly alkaline environment,the drug-loaded gel beads have a higher drug release,while the drug release is slow in acidic conditions.The presence of EMF could accelerate the release of drug from the beads.By constructing the mathematical models,the drug release mechanisms could be obtained as follows,in simulated gastric fluid(SGF),the drug release mechanism from the beads was mainly dominated by Fickian diffusion,while in simulated intestinal fluid(SIF)or simulated colonic fluid(SCF),the release mechanism changed to be dominated by a combination of diffusion,swelling and erosion.Furthermore,in vitro cellular experiments confirmed that magnetic drug-loaded gel beads showed good inhibition of colon cancer cells(HCT116),while good biocompatibility with normal cells(3T3).Therefore,the obtained beads are expected to be the effective delivery platforms for oral drug delivery for targeted therapy of human colon cancer.