چكيده به لاتين
Alzheimer disease causes to central nervous system disorder. One of the challenges in the treatment of this disease is to deliver the drug molecules through the BBB (blood brain barrier). According to this thesis, drug loading process in nanocarriers of PBCA (poly n-butyl cyanoacrylate) and chitosan is investigated by molecular dynamics simulation. In summary, accumulation of polymer chain and encapsulation of drug molecules were evaluated individually in two part by relying on modeling of polymer chain length and emulsion polymerization process.
In the first study, MD simulations was used to investigate the behavior of the drug rivastigmine and its carrier so-called poly (n-butyl cyanoacrylate) in the encapsulation process. Polymer modeling, and subsequently the emulsion polymerization model, were applied to analyze drug release in vitro and to justify rivastigmine transport across the BBB and polymer agglomeration. On the other hand, suitable polymer chain length, encapsulation method, polarity between polymer and drug structure, and finally, pattern of drug released in vitro and in vivo were investigated to analyze the behavior of drug and polymer accurately. Maximum drug loading was determined based on the modeling of drug encapsulation and comparison of the radius of gyration of polymer (Rg) and distance between center of masses (COMs) of rivastigmine molecules and polymer in equilibrium condition (Å). With the aim of better understanding of drug release, we calculated the Flory–Huggins interaction parameter, diffusion coefficient, and intermolecular interaction energy. The results reveal that more drug molecules remain on the surface of the polymeric structure, with increasing the concentration of rivastigmine molecules, but the number of encapsulated drug molecules inside of the polymer remains constant. Also, calculated values of Gibbs free energy indicated that intramolecular interactions of the polymer chain overcome the intermolecular interactions between polymer and drug. Therefore, any extra loading of drug resulted in accumulation on the polymer surface.
In the second step, MD simulation was employed to scrutinize behavior of chitosan nanoparticles (CS-NPs) as a nanocarrier for donepezil and rivastigmine drug molecules. Accordingly, modeling of CS-NPs was carried out based on experimental method (i.e., spontaneous emulsifications). The comparison of Rg of chitosn and equilibrium distance (r) of donepezil molecules indicated that CS-NPs is spherically agglomerated before and after addition of ions. However, the behavior of CS-NPs as carrier of rivastigmine molecules changed after addition of ions. The use of CS-NPs length in three dimensions (xyz) and the nearest distance of COM of drug molecules relative to the CS-NPs (rd) demonstrate that entanglement of polymer chains is decreased. Furthermore, behavior of the polymer is confirmed by intra- and/or inter-molecular interactions analysis of components of systems (i.e., CS-NP, drug molecules and ions) and diffusion coefficients of drug molecules. In this regard, the slope of MSD curve versus time is sharply increased in presence of ions in rivastigmine systems due to opening of polymeric chains and release of some of drug molecules. Therefore, drug loading capacity in CS-NPs is decreased in rivastigmine systems relative to donepezil systems. This assessment showed good agreement between results of MD and others experimental work.
