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キーワード:
molecular modelling, coarse-grained simulation, chitosan hydrogen, drug delivery, molekulare Modellierung, grobkörnige Simulation, Chitosan-Hydrogel, Wirkstoffabgabe
要旨:
Carbohydrates are class of biomolecules- their functions and properties cover a vast field that still needs to be explored. Many biological polysaccaharides form aggregates and their structures and properties are very versatile and depend on the aggregate structure and molecular interactions. Natural polysaccahrides can also form hydrogels, a porous network of polymers, that can take up a high percentage of water. Their properties can be additionally tuned by the introductions of chemical modifications to a fraction of monomers. To make efficient use of their versatile properties, understanding the relationship between the molecular structure and interactions of polysaccahrides and the properties of the aggregates formed is essential.
Computational modeling provides an efficient tool for understanding interactions at the molecular level, thus providing a qualitative direction for future experiments. Hence modeling offers a cost and time-efficient method for their study. In this thesis, the aggregates and structures formed by different glucose and chitosan oligomers were simu- lated and the resulting solution or aggregates structures are characterized using all-atom and coarse-grained molecular dynamics. Usually, polymers have slow dynamics making all-atom simulation computationally inefficient. Therefore a coarse-grained model was developed to study the properties of the polysaccahrides at the required length and time scale.
Chitosan hydrogels with various hydrophobic modifications were modeled. The trans- ferability of short oligomers with respect to different water concentration, degree of poly- merization and modification were explicitly established. Different morphological network structures of longer polymer were obtained corresponding to a different degree, type, and pattern of modification. In particular, a different morphological transition from a uniform polymer network to a structure containing dense hydrophobic cluster and large pores was found for certain conditions.
Finally, one of the principle applications of the chitosan hydrogel as a drug carrier was explored. The molecules Doxorubicin(DOX) and Gemcitabine(GEM) were chosen as model drugs and their interactions with the different modified chitosan polymers have been thoroughly studied at all-atom and coarse-grained resolution. The diffusion of DOX and GEM through the different network morphologies formed by the hydrophobically- modified chitosan was found to show quite different, network-dependent trends. Whereas GEM migrates through all chitosan hydrogels freely irrespective of type and degree of modification. Placing the drugs together in the networks affects the diffusion behavior of both. The results demonstrate the potential of this computational tool in the systematic development of drug-loaded hydrogels for pharmaceutical applications.
