The Study Of Optimal Strategy And Transmembrane Transport Of Nanomaterials By Using Dissipative Particle Dynamics Simulation

In recent years,nanomaterials have been widely used in many biomedical applications such as drug/gene delivery.The better understanding of the interaction between nanomaterials and cellular membranes can not only deepen the knowledge of some basis biological processes,but also provide useful guideline on the optimal design of nanomaterials.Recently,numerous efforts have been paid by both experimental and theoretical/computational researchers to the above key problem.For example,the molecular simulation can reveal the underlying mechanism of nanomaterials-cell membrane interactions at the atomic/molecular level,which can serve as a complementary method to the experiment.In this paper,dissipative particle dynamics(DPD)simulation was applied to simulate the interaction between different types of nanomaterials and cellular membranes to understand the molecular mechanism of transmembrane transport behaviors of nanomaterials,with the purpose of optimizing the nanocarriers of great targeting ability and high transmembrane efficiency.In the first chapter of this paper,the extensive application and research background of nanomaterials in biomedical field were described.Then we introduced the several stages of cellular transport of nanomaterials,especially the current situation and impacts of transmembrane transport.In the second chapter,the popular simulation methods and relevant theories for studying the interaction between nanomaterials and cellular membranes were introduced.We emphasized on the methods of dissipative particle dynamics as well as the selection of key parameters.Generally,nanoparticles with multi-ligand modification have higher cellular uptake capacity than the mono-ligand modification.However,it has been discovered that nanoparticles with dual-ligand modification did not always enhance the cellular uptake capacity in experimental work.For this reason,in the third chapter we systematically studied the interaction between dual-ligand modified nanoparticles and cellular membranes.It was found that the spontaneous rearrangement of dual ligands during the interaction process promoted the total engulfment of nanoparticles,while extremely short dual ligands refrained the rearrangement and resulted in the partial engulfment of nanoparticles.In addition,the length mismatch of the dual ligands and the nonspecific interaction between ligands also may inhibit the total engulftment.Through the analysis of the interaction mechanism between the ligands and the membranes,the Janus-type modification of dual ligands,which can fully exert the targeting ability of the two types of ligands,has been proposed to realize the efficient cellular uptake of dual-ligand modified nanoparticles.In the fourth chapter,we simulated the interaction of pH-responsive triblock copolymer micelles composed of ligand block(L),hydrophobic block(C)and polyelectrolyte block(P)with cellular membranes.It was found that the self-assembled large-volume pH-responsive micelle aggregated readily around the tumor tissues through enhanced permeation and retention effects.The weak acidic environment of tumor tissues leaded to the size switching of micelle(from large-size micelle to small-size micelles),which promoted the permeability of micelles in the dense interspace of tumor tissues.When small-size micelles interacted with the membranes,LCP-type micelles could perform the transmembrane transport through a series of processes,such as electrostatic adsorption,ligand-receptor binding,structural reorganization and penetration.In addition,the binding strength of ligand-receptor pair and block components also played an important role on the efficiency of transmembrane transport.Further,when the sequence of the L,P,C beads in the copolymers was changed,the transport pathways of the micelles may be changed from direct penetration to Janus-like engulfment.Based on the results,we gave the optimal strategy of micelles to meet the different transport requirements.In the design of micelles,the factors such as the triblock structure,components,pH-sensitive degree of copolymers and the binding strength of ligand-receptor pair must be considered comprehensively.Although ligand modified nanoparticles can achieve drug delivery to tumor cells,they are also adsorbed by normal cells and cause unnecessary toxicity and side effects.For this reason,in the fifth chapter we simulated the interaction of the copolymer modified nanoparticles conposed of protected receptor block and nonspecific block with two types of cellular membranes(normal cells and cancer cells).It was found that nanoparticles with non-covalent modification of copolymers could achieve both the total engulfment to tumor cells and blocked adsorption to normal cells,which is superior to nanoparticles with covalent modification of copolymers.In addition,appropriate binding strength between protected receptor and ligand,block components of copolymer,the repulsive parameters of nonspecific block were also the key factors to achieve targeting transport of nanoparticles.These results revealed the inherent molecular mechanism,and provided an optimal strategy for the targeting transport of nanoparticles.In the sixth chapter,our work was concluded,and an outlook of the future works in this field is described.