bologna tanis

Atomistic molecular dynamics simulations of dendrimers and their complexes with linear polyelectrolytes: 

Atomistic molecular dynamics simulations of dendrimers and their complexes with linear polyelectrolytes Ioannis Tanis,Kostantinos Karatasos Aristotle University of Thessaloniki, Department of Chemical Engineering Thessaloniki,Greece

Dendrimer Architecture: 

Dendrimer Architecture Central core molecule acts as the root from which a number of highly branched, tree-like arms originate in an ordered and symmetric fashion For each additional generation that is being added to the structure, the reaction sequence is repeated Stepwise method of synthesis results in a well defined size and low polydispersity C. Dufe`s et al. / Advanced Drug Delivery Reviews 57 (2005) 2177–2202

Complexation: 

Complexation Decrease of cytotoxicity Cell viability Low viscosity Complex can easily be transported in the blood Interpolyelectrolyte complex (IPEC) formation originates predominantly from the electrostatic interactions between oppositely charged groups as well as hydrogen bond formations Advantages Macromolecules, Vol. 33, No. 16, 2000

Applications in drug delivery: 

Applications in drug delivery Entrapment of drugs within the dendritic architecture Interaction between a drug and the surface of a dendrimer Results Increase of solubility Decrease of toxicity and dosage Control over drug release Oct. 2005 DNT Proprietary Targeted Diagnostic and Therapeutic Delivery Technology Dendrimer-drug interactions

Slide5: 

Encapsulation through hydrogen bonding Supramolecular Chemistry, Vol.18 (8), 636 (2006)

Aims of the work: 

Aims of the work Parameters that influence the ability of aqueous solutions of dendrimers or complexes of them with linear polyelectrolytes to act as solubility enhancement agents Mechanism of hydrogen bond formation between solvent molecules and polymer functional groups Degree of penetration of solvent molecules in the interior of the dendrimer Properties related to the capacity of dendrimers and their complex solutions to adsorb/release polar molecules in a controlled manner

Slide7: 

PAMAM (Polyamidoamine) Dendrimer C. Dufe`s et al. / Advanced Drug Delivery Reviews 57 (2005) 2177–2202

Models under study: 

Models under study Fully atomistic systems of 3rd ,4th and 5th generation PAMAM dendrimers with explicit water Fully atomistic system of pure water Fully atomistic complex systems of 3rd, 4th and 5th generation PAMAM dendrimers with explicit water and polyethylene oxide (PEO) All models at density 0.98 g/cm3 PEO PAMAM

Methodology: 

Methodology Construction of initial configurations Energy minimization through steepest descent and conjugate gradient techniques Charge assignment to polymer molecules through Gasteiger method. Water was modeled according to TIP3P. AMBER force field was chosen to describe the energy terms of the systems considering extra hydrogen-bonding term. Input files for DL_POLY

Initial Configurations: 

Initial Configurations G3-H2O G4-H2O G3-PEO-H2O G4-PEO-H2O G5-H2O G5-PEO-H2O

Simulation Details: 

Simulation Details 1st part: 3rd and 4th generation systems were subjected to equilibration runs in the NPT ensemble with 1fs time step Resources: 8 Linux boxes (processors from 2.66 to 3.0 GHz) located in Aristotle University of Thessaloniki

Simulation Details: 

Simulation Details 2nd part: Production runs of 4ns for 3rd and 4th generation. Generation 5 systems were only brought to equilibrium due to CPU time limitations Resources: 20,000 CPU hours in SGI Altix 3700 system (ASTER) located in SARA/Amsterdam

Static properties: 

Static properties Radial distribution function of water in all systems

Dynamic properties: 

Dynamic properties Autocorrelation function of the mean squared radius of gyration of dendrimer at systems G3-H2O, G3-PEO-H2O (left), G4-H2O and G4-PEO-H2O (right)

Dynamic properties: 

Dynamic properties Autocorrelation function of the mean squared radius of gyration of dendrimer at systems G3-H2O, G4-H2O (left), and G3-PEO-H2O, G4-PEO-H2O (right)

Relaxation Times: 

Relaxation Times The presence of the linear chain results in increase of the relaxation time in complex systems The relaxation times show that the simulation times are long enough to sample independent configurations

Hildebrand’s Solubility Parameter: 

Hildebrand’s Solubility Parameter In atomistic simulations for polymeric materials, the cohesive energy is defined as the increase in energy per mol when all intermolecular forces are removed The solubility parameter is defined as the square root of the cohesive energy density Calculated value of solubility parameter of pure water: 23.8 (cal/cm3)1/2 Agreement with experimentally measured value 23.4 (cal/cm3)1/2 Organic Electronics, 7, 5, 271 (2006)

Ongoing Research: 

Ongoing Research Development of a code to calculate the radial distribution function between elements that form hydrogen bonds. Simulation of systems of multiple PAMAM dendrimers Investigation of possible increase of water solubility by the inclusion of dendrimer or complex with PEO and study of its dependence on dendrimer or complex concentration

Summary/Conclusions: 

Summary/Conclusions Force-field is adequate to model the energy of studied systems In 4th generation systems, the number of hydrogen bonds increases significantly Simulation time was enough to obtain statistically reliable results

Future work: 

Future work Simulation of charged complex systems Study of the complex formation between a PAMAM dendrimer and a drug molecule and determination of the parameters that govern absorption/release of it by the dendrimer

Acknowledgements: 

Acknowledgements HPC-EUROPA translational access visit significantly enhanced the project through the use of supercomputing facilities and interaction with academic stuff with large experiments in molecular dynamics simulation The financial support of the Research Committee of Greece Co-workers

Slide22: 

Thank you for your attention!