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Evaluation of 100-nm-size mechano-responsive liposomes for targeted delivery at constricted arteries

Buscema, Marzia Maria Gaia. Evaluation of 100-nm-size mechano-responsive liposomes for targeted delivery at constricted arteries. 2018, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_12939

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Abstract

Today, cardiovascular disease remains the foremost cause of death worldwide. More than 70% of all cardiovascular diseases are due to dysfunction of the coronary arteries, which fail to supply sufficient oxygen to the heart. As first aid, the intravenous injection of a vasodilatory drug improves the survival rate. The dose, however, is limited because of side effects including a drop in blood pressure. Hence, a targeted instead of a systemic delivery is highly desirable. Recently, mechano-responsive liposomes about 100 nm in diameter have been proposed to transport the drug to the constrictions and preferentially release the vasodilator locally.
In order to pave the way for mechano-responsive nano-containers towards patient treatment, the present thesis contains studies on (i) the morphology of a plaque-containing human coronary artery throughout the preparation steps towards histology, (ii) the structural alterations of the liposomes under selected flow conditions, and (iii) the immunological response of the drug-loaded liposomes in vitro and in vivo.
High-resolution hard X-ray tomography in absorption and phase contrast modes have shown that paraffin embedding gives rise to an anisotropic shrinkage by 15 to 65% with respect to formalin fixed tissues. The decalcification procedure compromises the determination of the lumen, leaving remaining components of the plaque abound in the artery's lumen. Consequently, the lumen should be extracted before decalcification and paraffin embedding. For this purpose, phase tomography is much better suited than the conventional attenuation-based approach because of the minor dependence on the atomic number and the related reduction of streak artefacts.
The combination of spatially resolved small-angle X-ray scattering with microfluidics allows for the measurement of mechanically induced morphological changes of liposomes. Here, local changes in the average bilayer thickness and the mean size of the mechano-responsive liposomes have been detected. Overall shape and bilayer thickness do change already near the inlet to the constriction, but are dominant near the outlet. At a flow rate of 0.2 microliters per second, the liposome's bilayer thickness increased by 30% compared to the thickness well before the constriction and under static condition. The increase is in line with a mechanically induced loss of interdigitation between the phospholipid acyl chains.
The immune response to dedicated nitroglycerin-loaded, mechano-responsive liposomes has been quantified by means of enzyme-linked immunosorbent assays in vitro and by monitoring the arterial pressures in pigs in vivo. The research findings show comparable or less complement activation than the Food-and-Drug-Administration-approved liposomal drugs Abelcet and Doxil. Even an up to three times human therapeutic dose does not increase the pulmonary artery pressure and the systemic arterial pressure.
The results of the three subprojects demonstrate that physical approaches using smart containers of nanometer size can establish a groundbreaking background for the translation of basic science towards future patient treatments.
Advisors:Müller, Bert and Dommann, Alexius-Jean
Faculties and Departments:03 Faculty of Medicine > Departement Biomedical Engineering > Imaging and Computational Modelling > Biomaterials Science Center (Müller)
05 Faculty of Science
UniBasel Contributors:Müller, Bert
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12939
Thesis status:Complete
Bibsysno:Link to catalogue
Number of Pages:1 Online-Ressource (xii, 94 Seiten)
Language:English
Identification Number:
Last Modified:01 Feb 2019 05:30
Deposited On:31 Jan 2019 10:18

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