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Polymer-drug delivery. Combining computer simulations and experimental techniques

Meleshko, Glib 2015. Polymer-drug delivery. Combining computer simulations and experimental techniques. PhD Thesis, Cardiff University.
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The conformation that polymer-drug conjugates form in solution have a significant effect on properties that are important for designing of drug delivery systems. For N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer conjugates it is known that aggregation number, size and shape affect the rate at which a drug is enzymatically cleaved from the polymer backbone. Investigation of conformational properties could lead to creation of polymeric systems with the ability to keep drug levels at biologically active and safe concentrations for desired period of time. This project is focused on establishing the required modeling methodologies to describe the solution configurations of HPMA based conjugates. Therefore structural properties such as size, shape and density distribution of a range of HPMA copolymers have been investigated. The suitability of atomistic force fields has been assessed against rotational barriers and relative conformational energies obtained from ab initio and DFT data for a monomer and dimer of HPMA. Following this, the AMBER99 parameter set was chosen for all molecular dynamics simulation. Radius of gyration (Rg), radial distribution function (RDF), shape, and density profiles of particular atom types were calculated for a range of HPMA homopolymers sizes from 4 to 200 repeat units (2 to 35 kDa). Results were interpreted in the context of Flory’s mean field approach, and compared with data obtained from small angle neutron scattering (SANS) experiments. Results of this study were used for investigation of HPMA conjugates with drug mimics. A range of linear amines (aminohexane(C6), aminooctane(C8), aminododecane (C12)), hydroxyl and fluoro terminated linear amines as well as aromatic aminoanthracene (ANC), aminocrysene (AC) and aminoanthraquinone (ANQ), bound to the polymeric carrier via a tetrapeptide linker (glycinephenylalanine- leucine-glycine) (GFLG) (Mw ~ 30 kDa) were selected as model objects for study of the effect of drug type and loading on HPMA copolymer conformation. Using obtained results for further investigation we have progressed to more complex systems of mixed polymer conjugates containing drug-mimic parts with similar parameters of hydrophobicity, but different in terms of flexibility for drug-mimic chain. In order to provide corresponding comparison we have selected systems of Adamantane (Ad)/ANC, Ad/ANQ, methyl-Adamantane (AdMe)/C12, hydroxyl-Adamantane (AdOH)/C10OH and Ad/C10 conjugate iii mixtures and investigated the effect of changing ratio of drug-mimic parts for these systems. Analysis of SANS data revealed how conformation can be affected by the drug mimic’s intrinsic volume variation, and allowed us to get closer to finding answers for questions that can increase effective use of polymer-drug therapeutics. SANS experimental scattering curves were compared with theoretical curves, predicted from molecular dynamics (MD) simulations. Parameters such as size and shape fitted to SANS data were compared with relevant simulated structures. Based on results of previous studies as well as additional polymer synthesis and characterization process we were able to develop reliable all-atom (AA) and coarse-gain (CG) computer models for simulation of HPMA polymer. Required tools and software were developed. Various methods were used to increase performance efficiency of Molecular Dynamics calculations. Among them highest practical impact has a domain decomposition parallelization strategy.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Date of First Compliant Deposit: 30 March 2016
Last Modified: 20 Mar 2016 00:01

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