No description available.

Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 6 uppsatser.

Nanoparticles (NPs) use for drug delivery or vaccines is highly successful. Given this, optimizing a NP's biological identity for maximal therapeutic benefit remains challenging. Macromolecules absorption from biofluids by NPs forms a layer called the protein corona. Herein, we examined a corona's influence on the uptake of polymeric NPs, made with a hyperbranched polyester polymer (HBPE), by breast cancer cells. Moreover, a corona's ability to increase cancer killing through improved paclitaxel (taxol) drug delivery was evaluated. Normal and influenza A virus (IAV)-infected mice sera were employed as coronal protein sources. Pre-coating NPs with sera may enrich NP surfaces with proteins that favor cancer interaction. In turn, a NP's ability to reach tumors may be enhanced by exploiting normal or IAV sera content. For normal and IAV sera studies, polyethylene glycol (PEG), a gold-standard NP surface modification for in vivo delivery, served as a control to sera-incubated HBPE-NPs. Sera pre-coated HBPE-NPs exhibited enhanced breast cancer cell uptake and tumor localization, over PEGylated HBPE-NPs. Additionally, breast cancer treatment with sera pre-coated HBPE-NPs resulted in greater taxol-mediated killing compared to PEGylated HBPE-NP treatment. Sera pre-coated HBPE-NPs additionally demonstrated greater uptake in cancer cells in an in vitro transwell system. The transwell system involved NP treatment in an upper chamber containing endothelial cells and assaying NP uptake in a lower chamber containing cancer cells. IAV sera coating enhanced NP localization to breast cancer tumors, while lowering liver and spleen accumulation in mice. We show HBPE-NPs incubation with normal and immune response-derived IAV sera can form coronas with unique proteins. Our findings suggest that sera collected during an immune response to infection are a rich source of coronal proteins that could form the basis of a preformed protein corona that ensures the optimal biological identify for targeted cancer cell uptake as described herein.

Yes / Schizophrenia is a complex and unpredictable mental disorder which affects several domains of cognition and behaviour. It is a heterogeneous illness characterised by positive, negative, and cognitive symptoms, often accompanied by signs of depression. In this tutorial review, we discuss recent progress in understanding the target sites and mechanisms of action of second-generation antipsychotic drugs. Progress in identifying and defining target sites has been accelerated recently by advances in neuroscience, and newly developed agents that regulate signalling by the main excitatory neurotransmitters in the brain are surveyed. Examples of novel molecules for the treatment of schizophrenia in preclinical and clinical development and their industrial sponsors are highlighted. / The Royal Society, The Academy of Medical Sciences, The Wellcome Trust, The Government Department of Business, Energy and Industrial Strategy and the British Heart Foundation, The University of Bradford.

This research aims to evaluate two new pharmaceuticals on the market. Rimegepant and Lasmiditan target the trigeminovascular system and respectively, are characterized in the gepant and ditan classes of pharmaceuticals. Based on a review of studies, Rimegepant was determined to be the advantageous acute treatment. This is not conclusive due to inequivalent comparison in sample size and amount of research completed. It is encouraged for additional research to be imposed before a conclusive determination of the advantageous acute treatment can be distinguished.

L’ifosfamide (IFO) et le cyclophosphamide (CPM) sont des oxazaphosphorines, prodrogues nécessitant une bioactivation pour être actif. Dans le cas de l’IFO, sa biotransformation conduit à une faible libération du composé hydroxylé actif accompagnée d’effets secondaires toxiques. Des analogues préactivés de l’IFO avec des chaines C1-C30 saturées ou non ont été développés, afin de contourner ces toxicités liées à la voie toxicogène du métabolisme. Dans le cadre de la stratégie de pharmacomodulation de l’IFO, l’évaluation cytotoxique de ces composés synthétisés a été réalisée in vitro sur des lignées cellulaires cancéreuses humaines. Une étude in vivo du Géranyloxy-IFO, un candidat potentiel, a démontré un meilleur profil pharmacocinétique pour le G-IFO comparativement à l’IFO. Ces analogues ont ensuite été vectorisés sous forme de nano-systèmes, soit par auto-assemblage ou par encapsulation lipidique constituant des vecteurs de 1ère génération. Ceux-ci continuent d’être développés afin de leur conférer une spécificité par ciblage passif ou actif.Par ailleurs, le CPM est connu pour son activité sur le système immunitaire à faible dose. Au vue de la proximité structurale entre l’IFO et el CPM, nous avons étudié l’effet immunomodulateur de l’IFO à faibles doses, en comparaison à la dose immunomodulatrice du CPM.La combinaison de ces deux stratégies (préactivation & effet immunomodulateur) pourrait conduire au développement de nouveaux dérivés démontrant une synergie antitumorale des effets antiprolifératif et immunomodulateur de ces oxazaphosphorines. / Ifosfamide (IFO) and cyclophosphamide (CPM) are oxazaphosphorines, prodrugs requiring bioactivation to be active. Regarding IFO, its biotransformation leads to a low release of the active hydroxylated compound with associated toxic side effects. Preactivated IFO analogs with saturated or unsaturated C1-C30 chains have been developed to circumvent these toxicities related to the toxicogenic pathway of metabolism. As part of IFO's pharmaco-modulation strategy, the cytotoxic evaluation of these compounds, synthesized by engraftment of poly-isoprenyloxy chains, was carried out in vitro on human cancer cell lines. In vivo study of the lead shows the better pharmacokinetic profile of Geranyloxy-IFO compared to IFO. These analogs were then vectorized as nanosystems, either by self-assembly or by lipidic encapsulation leading to 1st generation nanosystems. They are still under investigation in order to bring specificity by passive or active targeting.Furthermore, CPM is known for having an activity on the immune system at low dose. Due to the structural proximity of IFO and CPM, we fulfilled studies to highlight the effect of IFO on the immune system at low dose in comparison to the immunomodulatory dose of CPM.The combination of these two strategies (preactivation & immunomodulatory effect) could lead to the development of novel derivatives showing an antitumor synergy of the antiproliferative and immunomodulatory effects of these oxazaphosphorines.

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Diss. (sammanfattning) Uppsala : Univ., 2001. / Härtill 4 uppsatser.