Theoretical And Computational Investigations Of Cell-nanoparticle Interactions

Nowadays, nanotechnology has emerged as an important role in many areas of science and technology. Nanomedicine, as one of the fastest growing applications of nanotechnology, has attracted a lot of interest. Compared with traditional materials, it is believed that nanomaterials have numerous advantages over them in bio-sensor, cell imaging and drug/gene delivery due to their unique physicochemical properties. Thus, a better understanding of the molecular details of interactions between nanopar-ticles and biological systems (especially cells of different types) is of great importance to make the best use of nanoparticles (i.e., increasing the delivery efficiency while decreasing the potential toxicity). In this thesis, we will investigate the interaction be-tween nanoparticles and cells by using computer simulations and theory, and wish our results can provide useful guideline for future experimental design of nanomaterials from the microscopic (and/or mesoscopic) view.In chapter 1, we briefly introduce the present status of nanomaterials and nan-otechnology in biomedicine. Moreover, we describe the whole in vivo delivery process of nanomaterials (including intracellular and extracellular delivery), and point out the main translocation barrier. As one of the most important step, how nanoparticles cross the cell membranes is detailedly discussed. Further, we also illustrate the structure, compositions and functions of the cell membranes.In chapter 2, we give a brief introduction of the typical simulation and theory method in modeling nanoparticle-membrane interactions. Then we describe some of molecular simulation method (like monte carlo, molecular dynamics, and Brown dy-namics) in short. Moreover, we pay special attention to describing dissipative dynam-ics (DPD) method in details, including its main ideas and how to choose parameter in DPD. Further, the Helfrich membrane theory is introduced and we also give the simple formulation under symmetric conditions.In chapter 3, we successfully design one new type of nanoparticles that can spon-taneously penetrate through membranes by adopting a reversible reaction between nanoparticle and ligands. It is found that the properties of ligands and nanoparticles constructing the nanoparticle-ligand complex (NLC) can affect their penetration effi-ciency and translocation time, and especially for nanoparticles with anisotropic shape or asymmetric surface decoration, the penetration efficiency can reach about 80% when NLC has the effective bullet-like shape oriented in a certain direction. Furthermore, we also provide insights into the interaction between nanoparticles and asymmetric mem-branes and find that the membrane asymmetry can highly affect the nanoparticle pen-etration and increase the penetration efficiency to above 90% under proper situations. We believe that this type of novel nanoparticles with high penetration efficiency as well as low toxicity will have huge potential application in drug/gene delivery.In chapter 4, we investigate the receptor-mediated endocytosis by combing simu-lation and theory, and find that there are three different phases (i.e., weak adsorption, partial engulfment, and total engulfment) of nanoparticles interacting with the mem-brane, which depend on particle radius, ligand density and receptor density. And by using a kinetic model, we highlight the importance of fourth elasticity energy term in elastic bending energy during the endocytosis process. Moreover, in addition to the three stable phages (i.e., weak attachment, partial engulfment, and total engulfment) which have been found in the interactions between rigid particles and membranes, there exists another state named after "frustrated engulfment" between ligand-coated nanoparticles and membrane, which is originated from the spontaneous lack of ligands during the engulfment process. Increasing the strength of the receptor-ligand interac-tion in this situation cannot increase the engulfment degree, while increasing the lig-and density and rigidity or changing the hydrophobicity/lipophobicity of ligands can increase the engulfment degree and may induce the total engulfment of the particle. Our results may be of great importance in engineering new types of nanoparticles to achieve optimal functionalities for biomedicine applicationIn chapter 5, we show that there exist two different modes (i.e., insertion and engulfment) in the interactions between Janus particles and membranes by using dissi-pative particle dynamics. For the insertion mode, the hydrophobic part of the particles inserts into the interior of the lipid bilayers and the hydrophilic part stays in the wa- ter; for the engulfment mode, the hydrophilic part is engulfed by lipid heads due to receptor-ligand bonds and the hydrophobic part is "engulfed" by lipid tails because of hydrophobic interactions. Moreover, we find that the initial orientation and the prop-erties of Janus particles have an important effect on the interactions. If the hydrophilic part is close to the membrane, the particle is more likely to be engulfed by membranes; however, even though the hydrophobic part is close to the membrane, the probability of engulfment may also be higher than that of insertion. For a particle with a large cross-sectional area, the initial orientation matters less for the interactions and particle is more likely to be engulfed. Finally, we point out that in the engulfment mode the particle-lipid-raft complex can detach from the membrane under small stimulus while in the insertion mode the complex is not so easy to detach.In chapter 6, we report one new type of pH-responsive drug delivery system con-taining pH-sensitive polymers with the help of computer simulation. The pH-sensitive polymers are able to spontaneously "coat" and "uncoat" on the nanoparticle surface under different pH environments, which in turn can regulate the interactions between nanoparticles and cell membranes. Therefore, they can be used to well control the cellular uptake of nanoparticles. More importantly, it is found that the uptake behav-iors here show triple-pH-responsive, i.e., under lower and higher pH conditions, the nanoparticles can be taken up by cell membranes, while for pH in middle range, the endocytosis process is blocked. The designed nanomaterial with triple pH-responsive property may have some advantages over previous experimental pH-responsive mate-rials in multi-pH systems. Further, it is found that receptor-ligand interactions as well as surface charge property of nanoparticles and membranes can also have important impacts on the endocytosis. The present study may give some significant insights into future stimulus-responsive medical materials design.In chapter 7, through dissipative particle dynamics simulations, we show that the presence of DNA on the nanovector surface may have different effect on the cellular uptake of nanovectors, i.e., when surface polyelectrolyte (PE) length is short, it may prevent the interaction between the ligands and receptors, which in turn could block the endocytosis; while for PE with longer length, it can make the ligands distributed uniformly on the nanovector surface so that it can help the cellular uptake; but when the length is very long, DNA may have little effect. Further, we find that the DNA concentration and PE density as well as DNA length could affect the endocytosis, and there may exist the optimal match between the DNA and PE length. We also provide the insights into the effect of PE protonation degree (i.e., external pH) and membrane charge property on the endocytosis, and importantly, it is found that the uptake effi-ciency of cancer cells should be higher than normal cells due to its low pH environ-ment and negative charged membranes. Generally, the present study will provide some useful guidelines for designing the gene nanovector with high transfection efficiency in future experiments, and may be of great importance in engineering new types of stimulus-responsive materials for biomedicine application.In chapter 8, we have investigated the protein adsorption on nanoparticle surface and its effect on cellular delivery of nanoparticle through dissipative particle dynamics simulations. It is found that the adsorption of protein on nanoparticle surface is depen-dent on its surface properties and external environments (e.g., pH), and the HSA can only adsorb onto charged nanoparticles and hydrophobic ones to form protein corona. More importantly, we have pointed out the distinct roles of protein corona in the cel-lular delivery at different stages, which is also related to the original surface properties of nanoparticles (i.e., charge property and hydrophobicity). When interacting with macrophage cells in the blood (or immune system), the adsorption of protein onto NP surface may change the mode of macrophage cell-hydrophobic nanoparticle interac-tion while it can enhance the phagocytosis of positive nanoparticles, meaning that it can have great impacts on the immune response to nanoparticles. When the NP inter-acts with targeted cells in tumor tissues, we find that the cellular uptake efficiencies (of hydrophobic and positively charged nanoparticles) may both become lower in the pres-ence of HSA protein no matter what the original uptake pathways are. In general, our results have exposited the underlying mechanism of the problem (i.e., why the uptake levels are very different for different nanoparticles and cell systems, in the presence or absence of proteins) and may provide significant ideas for engineering new types of nanomaterials in biomedicine.In chapter 9, the thesis is summarized, and a outlook for the future works in this field is described.