Molecular Dynamics Simulation And Mechanism Analysis Of The Self-Organize Process Of Hydrophobic Nano-Drug Particles

Hydrophobic nano-drug particles are susceptible to aggregation,recrystallization and Oswald ripening.Experiments have shown that the hydrophobic anti-cancer drug,paclitaxel?PTX?,can cross-link with tannic acid?TA?,and the self-assembly structure of PTX and TA can be manipulated by adjusting the pH value of the system.In experiments,when TA molecules are adsorbed to the surface of PTX at a pH of less than 3,they could not inhibit the Ostwald ripening of PTX.With 3<pH<6,TA molecules exist as dimers with the addition of Fe³⁺.The formation of a stable protective film with a certain thickness on the surface of PTX can thus result in the long-term stable hydrophobic nano-drug spherical particles.With 6<pH<7,under the mediation of Fe3+,TA molecules exist as trimers;both PTX and TA molecules self-aggregate respectively,thus could not inhibit the Ostwald ripening of PTX.The process and underlying mechanisms of the self-assembly of the system are analyzed to guide the relevant experiments.Considering that none of the existing atomic models could describe the force field parameters of Fe³⁺,a multi-scale simulation method is utilized in this work through the development of a coarse grained model which is based on the Fe³⁺-mediated mesoscale structure form by the TA molecules.The specific implementation of the multi-scale simulation method is as follows:first,through the all-atom molecular dynamics?AAMD?simulation,the lowest energy structure of the single molecule of PTX and TA is determined;then,according to the concentration in experiments,a similar AAMD simulation is performed,and the properties of the system,including energy,hydrogen bonding,and interfacial area are analyzed for general understanding of the phenomena at microscale.Then,coarse grained?CG?molecular model of PTX and TA are developed based on the table structures obtained from AAMD.Further,the mesoscale model of the complex formed by TA molecules and Fe³⁺are developed based on the results of AAMD and quantum mechanics?QM?simulations,resulting in the CG model of TA dimer and TA trimer for3<pH<6 and 6<pH<7 respectively.Finally,coarse grained molecular dynamic?CGMD?simulation are carried out using this coarse-grained model,the three systems of PTX and TA with different pH values are simulated,and the underlying mechanisms are discussed based on the comparison of the simulation results and corresponding experiments.The results are as follows:When pH<3,PTX molecules evolve into a rod-like structure,with TA adsorped as a monolayer on the surface of PTX.When3<pH<6,PTX molecules evolve into a spherical agglomerate and TA adsorb to the surface of PTX.When 6<pH<7,PTX and TA molecules aggregate into clusters respectively.The above simulation results are basically consistent with the experimental results,which preliminarily verifies the accuracy of the CG model developed in this paper.On this basis,the system energy,surface area of the aggregations and evolution dynamics of the self-assembly process are analyzed,and compared with the AAMD simulation results and experimental results to explore the underlying mechanisms of the system.Two dominating mechanisms are identified in the system,the first one is the adsorption of active molecules?TA?to the hydrophobic nano-drug particles?PTX?,and the second one is self-aggregation of the active molecules in bulk.The dominance of mechanism 1 over mechanism 2 would result in rod-like hydrophobic particles with adsroption monolayer;vice versa,the dominance of mechanism 2 over mechanism 1would result in self-aggregation of the two components respectively.Only through compromise in competition of these two mechanism could obtain spherical hydrophobic nano-drug particles.In this paper,the CG molecular models of PTX and TA molecules are successfully developed for further simulations of the self-assembly process.The simulations of self-assembly of hydrophobic nano-drug particles are performed and the mechanisms are further discussed.,which could also serve as a reference for more simulations of the anti-cancer drug particles with similar components of bio-molecules.