The use of molecular dynamics simulation for the study of polymeric and lipid based drug delivery systems

Systemic administration is the conventional method for administrating drugs. Following injection, ideally, we wish the drug only to locate to the target tissue, however, this is not what occurs; the drug molecules rather distribute throughout the entire body via the blood stream. Regarding some drugs, in particular chemotherapy agents, this often leads to severe dose limiting side effects and unsatisfactory therapeutic results. On the other hand, many drugs as is also the case for the chemotherapy agents, demonstrate low aqueous solubility and suboptimal pharmacokinetic properties. These problems all necessitate the use of drug delivery systems (DDSs) as they decrease the side effects of drugs while also improving drug bioavailability and pharmacokinetics. Although there are different varieties of DDSs, we have focused on those categorized as polymeric or lipidic. Depending on the drug to be delivered and site of action of the drug, polymeric DDSs can be used either locally or systemically. Hydrogels and electrospun polymer fibers are two examples of polymeric DDSs that are used for the local delivery of many drugs, including antibiotics and anticancer drugs. The other form of polymeric DDSs are nanoparticles that are capable of carrying and in some cases targeting drug molecules. These polymeric DDSs are generally injected into the blood stream to reach their target site. Lipidic DDSs mainly are used in the form of nanoparticles that, depending on their lipid composition and method of preparation, would have different characteristics. Liposomes and solid lipid nanoparticles are two examples of lipidic DDSs. Despite the huge number of publications regarding the use of nanoparticles as DDSs, the number of approved drug therapies that make use of nanoparticle-based delivery systems still remains small. One of the reasons for this problem is that formulations of DDSs are complicated and difficult to optimize. Drug delivery systems should be further redesigned and optimized, however, this has proved challenging due to intrinsic and practical experimental limitations. For example, it is difficult to experimentally elucidate the reason many DDSs show promise in vitro but fail in vivo. The limitations to the extent to which mechanistic insight can be gained from experiments regarding DDSs can be compensated by computational molecular modelling techniques that provide detailed information on molecular interactions of drugs and carriers. The insights obtained by the studies performed in this thesis can be used to improve the design of DDSs. In this thesis, two polymeric (studies I and IV) and two lipidic (studies II and III) DDSs were studied by all-atom molecular dynamics (MD) simulations. In each of these studies, a specific property of the DDS was evaluated in detail. These properties are drug release profile (study I), stability (study II), pH-sensitivity (study III) and size (study IV). We evaluated these properties through investigation of the three varieties of interactions DDSs have: interactions of DDSs with the loaded drug, interactions among the components of DDSs and interactions between the DDSs and the medium, namely water and ions. While it is difficult to directly determine an accurate picture of these interactions experimentally at atomic scale resolution, all- atom MD simulation can provide insight into this.Lääkeaineet annostellaan yleensä systeemisesti ja olisi ideaalista, että annostelun jälkeen lääkeaine vaikuttaisi vain paikallisesti kohdekudoksessa. Käytännössä näin ei kuitenkaan tapahdu, vaan pikemminkin lääkeainemolekyylit jakautuvat koko kehoon verenkierron mukana. Joidenkin lääkkeiden, erityisesti kemoterapeuttisten aineiden kohdalla, tämä johtaa usein vakaviin annosta rajoittaviin sivuvaikutuksiin ja näin ollen epätyydyttäviin terapeuttisiin tuloksiin. Toisaalta monilla lääkkeillä, kuten myös kemoterapia-aineilla, on myös alhainen vesiliukoisuus ja huonot farmakokineettiset ominaisuudet. Kaikki nämä ongelmat edellyttävät erilaisten lääkekuljetusjärjestelmien käyttöä, koska ne vähentävät esimerkiksi haitallisia sivuvaikutuksia ja parantavat lääkeaineiden biologista hyötyosuutta. Vaikka lääkekuljetusjärjestelmiä on erilaisia, olemme keskittyneet tässä väitöskirjassa vain niihin, jotka on luokiteltu polymeeri- tai lipidipohjaisiksi. Kuljetettavasta lääkeaineesta ja lääkkeen vaikutuspaikasta riippuen polymeeripohjaisia lääkekuljetusjärjestelmiä voidaan käyttää paikallisesti tai systeemisesti. Hydrogeelit ja sähkökehrätyt polymeerikalvot ovat esimerkkejä tällaisista lääkekuljetusjärjestelmistä ja niitä käytetään monien lääkkeiden, kuten antibioottien ja syöpälääkkeiden paikalliseen annosteluun. Polymeeripohjaiset nanohiukkaset pystyvät vuorostaan kuljettamaan ja joissakin tapauksissa myös kohdentamaan lääkeainemolekyylejä. Nanohiukkaset ruiskutetaan yleensä suoraan verenkiertoon, jotta ne saavuttaisivat terapeuttisen kohteen. Lipideistä koostuvat lääkekuljetusjärjestelmät ovat pääasiassa nanohiukkasia, joilla on lipidikoostumuksesta ja valmistusmenetelmästä johtuen erilaisia ominaisuuksia. Liposomit ja kiinteät lipidinanohiukkaset ovat esimerkkejä lääkeaineiden kuljetusjärjestelmistä, jotka pohjautuvat rasva-aineisiin eli lipideihin. Siitä huolimatta, että kirjallisuudesta löytyy valtava määrä tieteellisiä julkaisuja, jotka liittyvät nanohiukkasten käyttöön lääkekuljetusjärjestelminä, hyväksyttyjen nanohiukkaspohjaisten lääkehoitomuotojen määrä on edelleen pieni. Tämä johtuu siitä, että valmisteet ovat monimutkaisia, vaikeasti optimoitavissa. Nanohiukkasia tulisi edelleen suunnitella ja optimoida, mutta tämä on osoittautunut haastavaksi mittalaitteiden rajoituksien vuoksi. Esimerkiksi on erittäin vaikeaa selvittää kokeellisesti, miksi monet nanohiukkaset ovat lupaavia in vitro mittauksissa, mutta epäonnistuvat in vivo kokeissa. Kokeellisia mittauksia, joissa nanohiukkasista saadaan mekanistista tietoa, voidaan kompensoida erilaisilla in silico molekyylimallinnustekniikoilla, jotka tarjoavat yksityiskohtaista tietoa lääkeaineiden ja kantajien molekyylivuorovaikutuksista. Väitöskirjassa esitettyjä tuloksia voidaan hyödyntää lääkeaineiden kuljetusjärjestelmien suunnittelussa. Tässä väitöskirjassa tutkittiin kahta polymeereistä (tutkimukset I ja IV) ja kahta lipideistä (tutkimukset II ja III) koostuvaa lääkekuljetusjärjestelmää hyödyntäen atomistisia molekyylidynamiikka simulaatioita. Jokaisessa tutkimuksessa lääkekuljetusjärjestelmän tietty ominaisuus arvioitiin yksityiskohtaisesti. Näitä ominaisuuksia olivat lääkeaineen vapautumisprofiili (tutkimus I), stabiilius (tutkimus II), pH-herkkyys (tutkimus III) ja koko (tutkimus IV). Arvioimme näitä ominaisuuksia tutkimalla kolmea erilaista vuorovaikutusta lääkekuljetusjärjestelmissä: matriisin vuorovaikutus ladatun lääkkeen kanssa, matriisin eri komponenttien vuorovaikutus keskenään sekä vuorovaikutus lääkekuljetusjärjestelmän ja väliaineen (vesi ja ionit) välillä. Siitä huolimatta, että kokeellisilla mittauksilla on erittäin vaikeaa tuottaa atomitason kuva näistä vuorovaikutuksista, voidaan näistä saada laskennallisia molekyylidynamiikkasimulaatioita hyödyntäen hyvä käsitys

Induction of partial protection against Leishmania major in BALB/c mice by Leishmania tropica”

Leishmaniasis is a parasitic disease of man and other mammals. Immunity against leishmaniasis appears  to remain essentially species specific; however some cross-reactivity has been reported. The aim of this  study was analyzing cross-protection induced by Leishmania tropica (L. tropica) against Leishmania  major (L. major). BALB/c mice were infected with L. tropica in the footpad followed by a challenge infection  in the contra lateral footpad by L. tropica or L. major. Footpad thickness and parasite load in the footpad,  popliteal lymph node, and spleen were determined after challenge. The results demonstrate that L.  tropica induces partial protection of BALB/c mice against L. tropica as well as L. major. The  protection was more efficient against a homologous strain (L. tropica) than against a heterologous strain  (L. major). The partial protection against L. major was detected in the footpad tissues as well as popliteal  lymph node. No protection was observed against L. major in the spleen tissue. These findings have  implications in vaccination strategies for Leishmaniasis based on the use of heterologous species of the  parasite.

Optimal water allocation for joint sustainability of irrigated agriculture and urban growth

2017 Fall.Includes bibliographical references.Historically, agriculture was the main water consumer in Colorado. But the state's demand for water has increased because of rapid urban growth and development of oil and gas industry. Urban communities started buying agricultural water rights to satisfy their growing demands. However, alternative land uses for farms without water right are limited and often they are left fallow. Colorado's newly finalized water plan recognizes agriculture dry-up as one of the primary water challenges of the state and supports projects that explore alternatives to the permanent transfer of agricultural water rights to municipal and industrial users. This research has investigated deficit irrigation and limited irrigation strategies as methods of reducing farm water consumption as well as methods of temporary transfer of water, viable under Colorado's Water Law. These two sets of information formed a conceptual framework for defining an effective transfer method. An economic model was developed to determine optimal water partitioning between on-farm water uses and off-farm water renting. The model proves partitioning water is only optimal when crop water production function is concave; for linear functions the optimal option is to allocate all farm water to the most profitable. Field experimentation has determined the effect of water scarcity on agricultural production and revenue. In particular, crop yield response to water stress was quantified in experimental farms for three common crops in Colorado: corn, sunflower, and sorghum-sudangrass. The filed observations support a linear crop water production function for sorghum-sudangrass and a concave function for corn and sunflower with corn function being more concave than sunflower function. The economic model was used for South Platte River Basin to determine the minimum renting price of water for water partitioning to be optimal. The results show current renting prices of water in South Platte River Basin are too low and need to increase to more than six times before partitioning of water becomes a worthwhile practice. It was also concluded that two set of engineering tools are required for implementation of deficit irrigation; 1) tools to accurately apply desired amount of water, and 2) tools to measure farm consumptive use on a daily basis. At institutional level, Colorado Water Law's no-injury and anti-speculation rules need to be simplified for deficit irrigation to be a worthwhile alternative method to buy-and-dry

Effects of dietary Bacillus subtilis on growth performance and immune responses, in rainbow trout, Oncorhynchus mykiss (Walbaum, 1792)

Four hundred and eighty five rainbow trout (76 ± 6.44 g mean weight) were acclimated to laboratory conditions and then randomly divided into four groups of tanks in triplicate. The first group (Group 1) was fed on a commercial diet (control) without Bacillus subtilis supplementation. The second, third and fourth groups (Group 2, Group 3 and Group 4, respectively) were given a diet supplemented with 1, 5 and 10 g probiotic powder (containing 8×10^7 CFU g^-1 Bacillus subtilis) per kg commercial feed. Growth performance, immune responses and glucose levels were analyzed on days 0, 22 and 44. The results showed that dietary Bacillus subtilis supplementation significantly (p0.05) was observed in weight gain rate (WGR) between the control and group 2. On the effect of dietary Bacillus subtilis on serum lysozyme, it was observed that group 3 and group 4 did not show any significant differences in serum lysozyme activity and serum total antibody on day 44. Results of alternative complement activity, showed significant increase during the experimental days (p<0.05). Results on glucose assay showed that group 3 had the lowest glucose level (13.71 mg/dL) which was not significantly different than that in other groups on day 44. Fish diet supplementation with 5 g probiotic powder (Group 3) is preferable for immune system responses; however, high dose of Bacillus subtilis may be helpful to improve growth performance in rainbow trout, Oncorhynchus mykiss (Walbaum, 1792)

Evaluation of Interpolation and Registration Techniques in Magnetic Resonance Image for Orthogonal Plane Super Resolution Reconstruction

Super resolution reconstruction (SRR) combines several perspectives of an image (typically low resolution) in order to reconstruct a more complete and comprehensive (higher resolution) image. The aim is to use this concept on magnetic resonance imaging (MRI) data, for which the standard is to scan in several-plane orientation in a 2D fashion. As a result, clinical MRI, functional MRI (FMRI), diffusion weighted imaging (DWI)/diffusion tensor imaging (DTI), and MR angiography (MRA) tend to have high in- plane resolution but low resolution in the slice-select direction. By combining the 2 scans of the orthogonal plane, new 3D images can be reconstructed. This thesis addresses the principal problem of image quality and considers a novel SRR technique that uses the original information from 3 MRI plane orientations in order to enhance the resolution based on prior knowledge of scanning protocol as it relates to voxel resolution. The procedure for validating the MRI data algorithm is executed using MRI dataset of a human brain. The mean squared error (MSE) and peak signal-to-noise ratio (PSNR) were computed for quantitative assessment, whereas the qualitative assessment was performed by visually comparing the SR images to the original HR

A study of institutions in Dickens’s Bleak House as a representation of Foucault's disciplinary society

This study employs Foucault's views on the strategies of power to analyze that the institutional world of Bleak House makes a disciplinary structure. The intrusion of these institutions in all strata of society in the novel, from the aristocratic Dedlocks to the poor area of Tom-All-Alone shapes a panoptic structure in which everyone is visible through a permanent and omniscient gaze. Under the matrix of various institutions almost all the characters in the novel, directly or indirectly, are trapped and engaged. This study shows the modernity of Dickens views on power relations in society and gives readers new maps to read Bleak House and new perspectives from which to view it

Impact of information technology on productivity and efficiency in Iranian manufacturing industries

The aim of this paper is to assess the impact of information technology (IT) on the productivity and efficiency of manufacturing industries in Iran. So, the data will be collected from 23 Iranian manufacturing industries during ''2002-2006'' and the methods such as DEA and panel data used to study the subject. Results obtained by the above two methods represent that IT has a positive and statistically significant effect on the productivity of manufacturing industries. It will be more in high IT-intensive industries than the other industries. But, there is no significant difference between the growth of labor productivity in IT-producing and IT-using industries