Dissipative Particle Dynamics Simulations Of PAMAM Dendrimers As Delivery Vectors

In recent years,dendrimers have received extensive attention due to their unique structure and properties in drug delivery and gene therapy.The applications of poly(amido amine)(PAMAM)dendrimers in biomedicine and their interactions with various bioactive molecules in multi-scale computer simulations were reviewed in this thesis.Furthermore,in order to reveal the underlying physical mechanisms in the delivery process,dissipative particle dynamics(DPD)simulations were employed to investigate the effects of various related factors on the dendrimer complexes.This thesis provides some useful suggestions and guidance for the design and development of PAMAM dendrimer-based delivery systems.The loading and release behaviors of PAMAM dendrimers on the anticancer drug(doxorubicin,DOX)were studied.A coarse-grained(CG)model for PAMAM was firstly constructed,then the effects of PAMAM dendrimer generation(G)on DOX loading and the environment pH on DOX release were investigated.Simulation results showed that the CG PAMAM model reproduced correctly the conformational properties of dendrimers.Due to the differences in hydrophobicity of the components of the system,PAMAM dendrimers mainly encapsulate DOX into their internal cavities.G6 and G7 PAMAM dendrimers have better encapsulation efficiency for DOX because of their high porosity.Under the condition of physiological pH,PAMAM dendrimers cannot release DOX drug molecules;however,DOX molecules can be released rapidly from PAMAM dendrimers at low pH.Such phenomena are mainly caused by the protonation of the primary and tertiary amines in PAMAM dendrimers and the primary amines in DOX.The electrostatic repulsion between these charged groups will lead PAMAM dendrimers swelling immensely and their inner cavities being exposed,which promotes the release of DOX moleculles.These simulations revealed the loading and release mechanisms of PAMAM dendrimers on hydrophobic drug molecules at mesoscopic scale.Another CG model was built for single stranded DNA(ssDNA)and its accuracy was justified.Then the effects of solution pH,dendrimer generation and salt concentration on the structures of PAMAM dendrimer-ssDNA complexes were systematically investigated.In addition,we investigated the sizes and morphologies of the self-assembled aggregates formed by PAMAM dendrimers and ssDNA molecules at various dendrimer/ssDNA charge ratios.Simulation results revealed that ssDNA molecules were condensed and packaged significantly by PAMAM dendrimers at neutral or low pH.For the load of a certain length of ssDNA,considering the condensation capability and ss DNA penetration,there exists an optimal PAMAM dendrimer generation.The stability of ssDNA-PAMAM dendrimer complexes decreases with the increase of salt concentration.The charge ratios of PAMAM/ssDNA can be used to regulate the sizes and morphologies of their self-assembled aggregates.