Liposomal targeting of antimicrobial agents to bacterial infections

Failure of antimicrobial treatment is observed frequently in hospitalized patients resulting in morbidity and mortality, A possible way to improve antimicrobial treatment is the targeted delivery of antimicrobial agents, This thesis describes a study on tihe use of long-Circulating liposomes for the targeted delivery of antimicrobial agents to sites of bacterial infections, In this chapter an introduction is given on the use of targeted drug delivery in infectious diseases, which is followed by the aims and outline of this thesis

Targeted Delivery of siRNA

Therapeutic application of siRNA requires delivery to the correct intracellular location, to interact with the RNAi machinery within the target cell, within the target tissue responsible for the pathology. Each of these levels of targeting poses a significant barrier. To overcome these barriers several strategies have been developed, such as chemical modifications of siRNA, viral nucleic acid delivery systems, and nonviral nucleic acid delivery systems. Here, we discuss progress that has been made to improve targeted delivery of siRNA in vivo for each of these strategies

Liposome-encapsulated prednisolone phosphate inhibits growth of established tumors in mice

Glucocorticoids can inhibit solid tumor growth possibly due to an inhibitory effect on angiogenesis. The antitumor effects of the free drugs have only been observed using treatment schedules based on high and frequent dosing for prolonged periods of time. As long-circulating liposomes accumulate at sites of malignancy, we investigated the tumor-inhibiting potential of liposome-encapsulated prednisolone phosphate. Liposomal prednisolone phosphate could inhibit tumor growth dose-dependently, with 80% to 90% tumor growth inhibition of subcutaneous B16.F10 melanoma and C26 colon carcinoma murine tumor models at 20 mg/kg by single or weekly doses. Prednisolone phosphate in the free form was completely ineffective at this low-frequency treatment schedule, even when administered at a dose of 50 mg/kg. In vitro studies did not show an inhibitory effect of prednisolone (phosphate) on tumor cell, nor on endothelial cell proliferation. Histologic evaluation revealed that liposomal prednisolone phosphate-treated tumors contained a center with areas of picnotic/necrotic cells, which were not apparent in untreated tumors or tumors treated with the free drug. In conclusion, the present study shows potent antitumor effects of liposomal formulations of glucocorticoids in a low dose and low-frequency schedule, offering promise for liposomal glucocorticoids as novel antitumor agents.</p

Холотропное дыхание как метод реализации потенциала личности сотрудника

На сегодняшний день в организациях существует множество проблем, из-за которых возникают сложности как в управлении предприятием, так и в эффективной работе сотрудников. Для любого управляющего компанией важно, чтобы сотрудник был уверенным, умеющим нестандартно мыслить, инициативным, целеустремленным, но в большинстве случаев на предприятии такие сотрудники отсутствуют или их количество ограниченно. В любом сотруднике кроется творческая личность, которая не всегда может быть реализована на практике или же просто подавлена. Для того чтобы предприятие могло эффективно функционировать, важно, чтобы каждый сотрудник мог разобраться в своих проблемах и обрести внутреннюю гармонию, которая позволит ему настроиться на работу и выполнять ее эффективно. Методика холотропного дыхания может помочь личности реализовать свой скрытый потенциал. Цель работы: определить значимость методики холотропного дыхания в организации и выявить, какое влияние она оказывает как на сотрудников, так и на предприятие в целом. Методы исследования: анализ литера- туры по данной проблематике, аналитический метод. Результаты: выводы, полученные в данном исследовании, способствуют определению действенности методики холотропного дыхания и значимости ее применения в организации. Today there are many problems in organizations which lead to difficulties in the management of an enterpriseand in the effective work of the staff. For any company manager it is important that the employee wasconfident, able to think outside the box, initiative, committed, but in most cases such employees are absent ortheir number is limited. There is creative personality in any employee which can’t always be revealed or issimply suppressed. In order for a company to operate effectively, it is important that every employee couldunderstand their problems and find inner harmony, which will allow them to tune into work and perform itefficiently. The technique of holotropic breathwork can help the person to realize their hidden potential. Objective:to determine the significance of the technique of holotropic breathwork in the organization and itsimpact on the employees and the enterprise as a whole. Methods: review of the literature on this subject,data analysis. Results. The findings of this study help to identify the effective methods of holotropic breathworkand the importance of its application in the organization

Exosome mimetics: a novel class of drug delivery systems

The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics

Ligand-targeted liposomes directed against pathological vasculature

The development of liposomes targeted to angiogenic endothelial cells offers exciting prospects for intervention in cancer and inflammation. Several proteins are (strongly) over-expressed on angiogenic endothelial cells as compared to the quiescent endothelium, and could potentially serve as targets for site-specific drug delivery. In this contribution particular attention is given to the design of targeted long-circulating liposomes directed against the alpha v beta 3-integrin protein

A polymeric colchicinoid prodrug with reduced toxicity and improved efficacy for vascular disruption in cancer therapy

Colchicinoids are very potent tubulin-binding compounds, which interfere with microtubule formation, giving them strong cytotoxic properties, such as cell mitosis inhibition and induction of microcytoskeleton depolymerization. While this makes them promising vascular disrupting agents (VDAs) in cancer therapy, their dose-limiting toxicity has prevented any clinical application for this purpose. Therefore, colchicinoids are considered attractive lead molecules for the development of novel vascular disrupting nanomedicine. In a previous study, a polymeric colchicinoid prodrug that showed favorable hydrolysis characteristics at physiological conditions was developed. In the current study, this polymeric colchicinoid prodrug was evaluated in vitro and in vivo for its toxicity and vascular disrupting potential. Cell viability studies with human umbilical vein endothelial cells, as an in vitro measure for colchicine activity, reflected the degradation kinetics of the prodrug accordingly. Upon intravenous treatment, in vivo, of B16F10 melanoma-bearing mice with colchicine or with the polymeric colchicinoid prodrug, apparent vascular disruption and consequent tumor necrosis was observed for the prodrug but not for free colchicine at an equivalent dose. Moreover, a five-times-higher dose of the prodrug was well tolerated, indicating reduced toxicity. These findings demonstrate that the polymeric colchicinoid prodrug has a substantially improved efficacy/toxicity ratio compared with that of colchicine, making it a promising VDA for cancer therapy

Identification of Peptide Ligands for Targeting to the Blood-Brain Barrier

PurposeTransport of drugs to the brain is limited by the blood-brain barrier. New, specific brain endothelium ligands can facilitate brain-specific delivery of drugs. MethodsWe used phage display in an in situ brain perfusion model to screen for new brain endothelium peptide ligands. ResultsTwo phage clones, displaying 15 amino acid-peptides (GLA and GYR) that were selected for brain binding in the mouse model, showed significant binding to human brain endothelium (hCMEC/D3), compared to a random control phage. This binding was not seen for other human endothelial cells (HUVEC). Binding to hCMEC/D3 cells was dose dependent. When phage GLA and GYR were individually perfused through the murine brain, their ability to bind to the brain was 6-fold (GLA) and 5-fold (GYR) higher than the control phage. When compared to lung perfusion, phage showed an 8.5-fold (GYR) and 48-fold (GLA) preference for brain over lung compared to the control. ConclusionsThese results indicate that two new peptide ligands have been identified that may be used for specific targeting of drugs to the blood-brain barrier