Investigating The Interaction Mechanism Between Chitosan And Gene/drug Through Molecular Simulations

Cancer is difficult to be cured because of hard to detection,it has been one of the leading killers which threatens the health of the world's human beings.The efficacy of conventional chemotherapy is reduced due to the nonspecific distribution and therapid clearance of many anti-cancer agents.Consequently,lots of efforts have been devoted to the design of drugs for cancer treatment.The method of delivery the gene therapy drugs or anticancer drugs to the targeted cell via nanocarriers could avoidmultiple physiological barriers and reduce side effects of chemotherapy.It is expected to provide new solutions for cancer treatment.One of the biggest difficulties in the drug delivery process is how to delivery gene therapy drugs or anticancer drugs into targeted cells safely and effectively.Chitosan has been extensively studied as gene and drug carriers towing to the advantages of good biocompatibility and biodegradability.Understanding interaction mechanism between chitosan and gene/drug from molecular level is important in the design and application of chitosan-based drug/gene delivery systems.In this thesis,molecular dynamics?MD?simulations were performed to explore the feasibility of encapsulation polynucleotide through chitosan.The effects of functional groups in chitosan,polynucleotide base types and their chain length on the behavior of chitosan-coated oligonucleotides were also discussed.On this basis,MD simulations were also employed to investigate encapsulating and releasing the anticancer drug Doxorubicin?DOX?via chitosan.The encapsulation and release process with chitosan chains under different pH values were studied,and the effect of drug concentrations on encapsulation and release behavior were also discussed.Finally,we provided insights on the interaction between chitosan and boron nitride nanotubes?BNNTs?.When taking the application prospects of boron nitride nanotubes?BNNTs?in the field of drug delivery into account.The effect of chitosan's protonation and radius of BNNTs on interaction mechanism were revealed.After that,the chitosan-BNNTs complex carriers were used in drug encapsulation,and the transmembrane transportation of DOX using chitosan-BNNTs complex carriers were initially discussed.The major contributions of this work are as follows:?1?The dispersion of polynucleotides in–NH₃⁺chitosan is better than that in–NH₂and–NHCOCH₃ chitosan systems.The encapsulation capacity of polynucleotide by chitosan is mainly balanced by two factors:the strength of polynucleotide binding to chitosan and the tendency of self-aggregation of polynucleotide in the solution.For–NH₃⁺chitosan system,the self-aggregation of polynucleotide could be partially eliminated owing to the strong electrostatic interaction,especially the H-bond between–NH₃⁺group in chitosan and phosphate group in polynucleotide.The well dispersed of polynucleotides can improve the encapsulation of polynucleotides by chitosan,and the delivery and transfection efficiency of gene carrier would be enhanced.?2?The DOX molecules can be effectively released from chitosan nanocarrier under tumorous cell acidic conditions?pH=6.5?.The self-aggregation behavior of DOX molecules increases with decreasing p H value.There are two factors that cause the aggregation of DOX:1)the strength of DOX binding to the chitosan is greatly weakened,DOX molecules can no be adsorbed around the chitosan chains.2)Significantly stronger?–?stacking interactions occur between DOX molecules.When the system pH is high,due to the stronger chitosan-DOX interactions and the tendency of self-aggregation of chitosan in the solution,the DOX can be well encapsulated by chitosan chains.Furthermore,the aggregation effect of DOX would be enhanced with the increasing dose of DOX,it also reduces the efficiency of DOX encapsulation via chitosan.Moreover,the increase in drug loading was not improved significantly due to the aggregation of DOX.?3?The combination of chitosan and BNNTs can be affected by the protonation of chitosan and the radius of BNNTs.Due to the adsorption of water molecules,the size of chitosan is become large.Therefore,chitosan is difficult to enter into the small tube and can only externally adsorb to BNNTs.With an increase of BNNTs radius,the protonation of chitosan will affect the chitosan configuration and the binding energy between chitosan and BNNTs.As a result,the non-protonated chitosan chain could enter into the BNNT?14,14?completely,while only partially of the fully protonated chitosan chains could enter BNNT?14,14?.?4?The research results show that the chitosan-BNNTs complex carrier can quickly encapsulate DOX.Furthermore,MD simulation was employed to investigate the process of transport of DOX through the phospholipid bilayer via chitosan-BNNTs complex.It is found that phospholipid molecules have strong interactions with BNNT?14,14?.The phospholipid molecules can spontaneously enter into BNNT?14,14?while chitosan and DOX can be continuously excluded by the phospholipid molecules in the tube,and finally the chitosan is completely excluded from BNNT?14,14?.