Study On The Mechanism Of Adsorption Of Aminopyrimidines And Quinazoline Compounds On Graphene Oxide Sheet Structure

Graphene oxide?GO?is a derivative of graphene,has a high loading capacity,and can perform various functional modifications.GO non-co-bonded loads compounds can achieve efficient loading of the compounds without destroying the structure of the original compound.Based on the structure of GO,hydrophobic interactions,hydrogen bonds,?-?stacking,and cation-?bonds may occur during GO non-covalent adsorption of compound molecules.However,due to the lack of research on the mechanism of non-covalent adsorption of graphene oxide,the interaction between the forces is not clear.Therefore,the mechanism of GO non-covalent adsorption is studied,which could be beneficial to better understand the adsorption and transport of target compounds by GO carriers,and further improve development of GO-based carrier delivery systems.We first synthesized GO by the Hummers method,and then obtained a stable and homogeneous GO aqueous solution by mechanical stirring and ultrasonic stripping.It was confirmed by UV,IR,DSC,TEM imaging,particle size and Zeta potential characterization methods.Then,in conjunction with previous studies of GO-loaded well-soluble compounds by our group,we performed an in vivo release study of a GO-loaded insoluble compound delivery system to verify the release profile of the GO delivery system in vivo.Next,we selected several insoluble compounds such as Imatinib,Nilotinib,an amino pyrimidine nuclear structure,and Erlotinib,Gefitinib,Afatinib,a quinazoline nuclear structure,as model compound molecules for loading and in vitro release tests with graphene oxide to study the mechanism of GO non-covalent adsorption of compound molecules.Computer simulation also helps the validation process.The results show that the GO has particle size at 500 nm,PDI value at 0.273,and zeta potential at-30.1 mV.The generation of characteristic absorption peaks such as the C=O stretching vibration peak at 1732 cm^-1,the C-OH stretching vibration peak at 1403 cm^-1,and the CO absorption peak at 1229 cm^-11 and 1062 cm^-1in the infrared spectrum indicates that Oxygen functional groups are introduced into the carbon skeleton and graphite is oxidized to GO.In the UV spectrum,the GO solution has a distinct absorption peak at 234 nm and a shoulder peak at 300 nm,both of which are characteristic UV peaks of GO.TEM images show that GO is a translucent thin film lamellar structure with slightly zigzag folds at the edges.As a result of the in vivo release test of the GO delivery system,the T_1/2/2 of the sparingly soluble raw material group was 1.104±0.18 h,and the C_maxax was2.600±2.06 mg/L.But the poorly soluble compound which loaded by the GO carrier was not detected in vivo.In the previous tests,the well-soluble compounds supported by GO were released and detected in vivo.Therefore,we believe that the solubility of the compound and its binding force with the carrier play a crucial role in the release of the GO delivery system in vivo.The results of GO loading experiments showed that the maximum loading and entrapment efficiency of different types of insoluble model compounds with similar aromatic rings are similar.Therefore,we believe that the?-?stacking and hydrophobic interaction play a major role in the binding of the compound molecule to the carrier.In terms of in vitro release studies,Imatinib had a maximum cumulative release of 20%within 30 min at pH 1.0.At pH 8.0,40%was released within 30 min,and finally the cumulative release was 85%within 120 min.The situation with Nilotinib is similar to that of Imatinib but it is slightly smaller.Therefore,under the basic conditions,the release rate of the compound of amino pyrimidine structure is accelerated,and the maximum release amount is increased.But the quinazoline structure of Erlotinib,Gefitinib,Afatinib is the opposite.In the computer simulation test,the distribution of the charge of the compound shows that the aminopyrimidine structure molecules such as Imatinib and Nilotinib has three amino groups which can form hydrogen bonds and cation-?bonds,while the quinazoline structure molecules such as Erotinib,Gefitinib and Afatinib only have two of the amino groups.Therefore,the aminopyrimidine structure responds more sensitive to the pH changes of the environment.The charge distribution shows Imatinib?-0.63,-0.06,0.32?,Nilotinib?0.67,0.23,-1.0?,and Imatinib more easily binds hydrogen ions than Nilotinib to form cation-?bonds.When the environment changes from acidic to alkaline,the hydrogen bonding between the GO and the model compound gradually increases,and the cation-?bond gradually weakens,and the hydrogen bond and the cation-?bond act to antagonize and work together.This makes the noncovalent binding forces of imatinib and nilotinib with GO gradually weaken,while the noncovalent binding forces of erlotinib,gefitinib,afatinib and GO gradually increase.This affects the release of the compound from the carrier GO.In summary,we believe that?-?stacking,hydrophobic interactions,hydrogen bonds,and cation-?bonds may play an important role together during GO non-covalent adsorption of compound molecules.Among them,the role of?-?stacking plays the most important role.And,both the hydrogen bond and the cation-?bond play an auxiliary reinforcing role in the adsorption process of the model compound and the support GO,and the two are generally regarded as antagonistic.Therefore,in the development of GO delivery system,targeted compounds can be selected according to different situations to achieve the desired effect.