Study On The Mechanisms Of Endocytosis Of Drug-loaded Nanoparticles

Nanoparticle therapeutics shows amazing efficacy in tumor treatment nowadays,in which drug carriers(usually nanoparticles)are directly transported to the target cells to release drugs for treatment.The efficient entry of nanoparticles into the target cells is the key to improve the therapeutic effect and reduce the toxicity.Drug-loaded nanoparticles enter cells mainly through endocytosis,which is an important channel for the transmembrane transport of extracellular substances.In recent years,based on the experimental results,scholars had put forward many theoretical and computational models to explore the mechanism of endocytosis,but these models have many shortcomings.To overcome the shortcomings of existing models,this dissertation aims to establish a new endocytosis theoretical and computational models to analyze the mechanical mechanism of endocytosis of nanoparticles,and provide technical support for drug-loaded nanoparticles design.The main research results of this dissertation are as follows:(1)A new actin force model is proposed by comprehensively considering two actin force generation mechanisms of the actin network.Then,based on the co-rotational grid method,a coarse-grained finite element model for endocytosis of nanoparticle is established to simulate the endocytosis of circular rigid nanoparticles.The effects of actin force,osmotic pressure,cell carcinogenesis,asymmetry and dynamic growth of actin network on endocytosis are discussed.The results show that there is a critical size of nanoparticles.When the radius of rigid nanoparticles is less than the critical size,the internalization efficiency is the highest.The more malignant the tumor cells are,the higher the internalization efficiency of nanoparticles is.There may be nanoparticles of critical size that can only be absorbed by tumor cells.The asymmetry of actin network and osmotic pressure will reduce the internalization efficiency of nanoparticles,but osmotic pressure will not affect the final configuration of endocytic vesicles.(2)A clathrin-coated growth model with actin force feedback is also proposed.Then,a coarse-grained finite element model is established to simulate the clathrin-mediated endocytosis of rigid nanoparticles with different shapes.The effects of clathrin coat growth,clathrin coat stiffness,the size and shape of nanoparticles on endocytosis are discussed.The results show that nanoparticle size is the main factor affecting endocytic behavior,and larger nanoparticles have higher transport efficiency but lower internalization efficiency.Increasing the clathrin coate stiffness and reducing the nanoparticles size both will reduce the transport efficiency of nanoparticles.Compared to rectangular nanoparticles,elliptical nanoparticles have higher internalization and transport efficiencies.(3)Based on the Abaqus simulation platform,the user-defined element(UEL)subprogram interface is used to realize the simulation of endocytosis of soft elliptical nanoparticles and nanoparticle clusters.The effects of nanoparticle entry angle,size,shape,stiffness and aggregation on endocytosis are discussed.The results show that the nanoparticle size is the main factor affecting the internalization efficiency of soft nanoparticles,followed by the aspect ratio and finally the entry angle.Compared with the single soft nanoparticle of comparable size,the soft nanoparticle cluster leads a lower internalization efficiency.The maximum radius of nanoparticles that can be absorbed by cells decreases with the decrease of the stiffness of nanoparticles.It means that the nanoparticles size should be reduced for the design of soft drug-loaded nanoparticles.(4)Based on the co-rotation grid method,a framework is established to model the dynamic growth and branching of actin filaments.Then,the dynamic growth of actin network has been successfully simulated.Besides,combined with the coarse-grained finite element model of endocytosis,the proposed algorithm has the potential to construct a complete framework for the study of endocytosis combining membrane mechanics and actin spatiotemporal dynamics,which could provide a basis for subsequent research.