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Sterically Stabilised Liposomes and Related Lipid Aggregates Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 629 _____________________________ _____________________________ Sterically Stabilised Liposomes and Related Lipid Aggregates Fundamental Studies on Aggragate Structure and Stability BY MARKUS JOHNSSON ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2001 Dissertation for the Degree of Doctor of Philosophy in Physical Chemistry presented at Uppsala University in 2001 ABSTRACT Johnsson, M. 2001. Sterically Stabilised Liposomes and Related Lipid Aggregates. Fundamental Studies on Aggregate Structure and Stability. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 629. 69 pp. Uppsala. ISBN 91-554-5027-X. Various aspects of and approaches towards the steric stabilisation of liposomes have been investigated, mainly by use of fluorescence techniques and cryo-transmission electron microscopy (cryo-TEM). It is shown that PEG(2000)-lipids can be incorporated in the liposome membrane up to a critical concentration of 8-10 mol% without any observable structural perturbations. Above 10 mol%, a breakdown of the liposome structure into flat lamellar discs was observed. The sterically stabilised liposomes displayed similar, or even reduced, membrane permeability as compared with conventional liposomes. The presence of PEG-lipids in the EPC membrane was shown to affect the liposome-to-micelle transition in mixtures containing OG. Little or no effects of the PEG-lipids were found on the transition in mixtures containing C12E8. The interactions between a number of PEO-PPO-PEO triblock copolymers and PC or PC/Chol liposomes have been investigated. It is shown that these polymers adsorb rapidly onto the liposome surface and induce a substantial increase in membrane permeability as well as structural perturbations. No evidence of an effective steric stabilisation due to the presence of the polymers at the membrane surface was found. This was shown, by the use of a QCM-technique, to be a consequence of the weak interaction between the polymers and the lipid membrane. Dispersions of reversed lipid phases in mixtures of DOPE and PEG-lipids were characterised using cryo-TEM. Dispersions displaying reasonable colloidal stability were obtained and particles exhibiting a periodic dense inner structure were observed. PEG-lipid micelles were characterised mainly using light scattering techniques. Micelle aggregation numbers and hydrodynamic radii were determined as a function of temperature. It is shown that the inter-micellar interactions are dominated by the steric repulsion. PEG-lipid stabilised liposomes loaded with boronated drugs intended for BNCT have been characterised. The drugs were efficiently encapsulated into the liposomes, resulting in a drug precipitation in the water core of the liposomes. Key words: Liposome, steric stabilisation, colloidal stability, cryo-TEM, drug delivery. Markus Johnsson, Department of Physical Chemistry, Uppsala University, Box 532, SE-751 21 Uppsala, Sweden © Markus Johnsson 2001 ISSN 1104-232X ISBN 91-554-5027-X Printed in Sweden by Akademitryck AB, Edsbruk 2001 List of papers The thesis consists of eight papers and a summary. The papers listed below are referred to in the text by their Roman numerals (I-VIII). I. Effect of Polyethyleneglycol-Phospholipids on Aggregate Structure in Preparations of Small Unilamellar Liposomes K. Edwards, M. Johnsson, G. Karlsson, M. Silvander Biophysical Journal, 1997, 73, 258-266 II. Effects of PEG-lipids on permeability of phosphatidylcholine/cholesterol liposomes in buffer and in human serum M. Silvander, M. Johnsson, K. Edwards Chemistry and Physics of Lipids, 1998, 97, 15-26 III. Interactions between Nonionic Surfactants and Sterically Stabilized Phosphatidyl Choline Liposomes M. Johnsson, K. Edwards Langmuir, 2000, 16, 8632-8642 IV. Effect of PEO-PPO-PEO Triblock Copolymers on Structure and Stability of Phosphatidylcholine Liposomes M. Johnsson, M. Silvander, G. Karlsson, K. Edwards Langmuir, 1999, 15, 6314-6325 V. Adsorption of a PEO-PPO-PEO Triblock Copolymer on Small Unilamellar Vesicles: Equilibrium and Kinetic Properties and Correlation with Membrane Permeability M. Johnsson, N. Bergstrand, K. Edwards, J. J. R. Stålgren Submitted to Langmuir VI. Phase Behavior and Aggregate Structure in Mixtures of Dioleoylphosphatidylethanolamine and Poly(Ethylene Glycol)- Lipids M. Johnsson, K. Edwards Biophysical Journal, 2001, 80, 313-323 VII. Spherical Micelles and Other Self-Assembled Structures in Dilute Aqueous Mixtures of Poly(ethylene glycol)-Lipids M. Johnsson, P. Hansson, K. Edwards Submitted to Journal of Physical Chemistry B VIII. Optimization of Drug Loading Procedures and Characterization of Liposomal Formulations of Two Novel Agents Intended for Boron Neutron Capture Therapy (BNCT) M. Johnsson, N. Bergstrand, K. Edwards Journal of Liposome Research, 1999, 9, 53-79 Reprints were made with permission from the publishers. Comments on my participation I performed most of the experimental work in Paper I, III, VI and VII. I performed ~half of the experimental work in Paper II, IV and VIII, and roughly one third of the experimental work in Paper V. I had the main responsibility of writing Paper III-VIII and I took part in writing Paper II and in the discussion of the results in Paper I. Contents 1. Introduction 7 2. Self-Assembly in Surfactant-Water Mixtures 9 2.1 Optimum Aggregate Structure 9 2.2.1 Surfactant Phase Behaviour 10 2.2.2 Hexagonal Phases 11 2.2.3 Cubic Phases 11 3. Lamellar Phases and Liposomes 13 3.1 Phospholipids 13 3.2.1 Phospholipid Lamellar Phases 14 3.2.2 Cholesterol in Phospholipid Lamellar Phases 15 3.3.1 Liposomes 16 3.3.2 Thermodynamics of Liposome Formation 16 3.3.3 Colloidal Stability 18 4. Experimental Techniques 21 4.1.1 Cryo-Transmission Electron Microscopy (cryo-TEM) 21 4.1.2 Artefacts in cryo-TEM 22 4.2 Intensity Light Scattering 24 4.3 Dynamic Light Scattering (DLS) 25 4.4 Fluorescence Measurements 25 4.5 Quartz Crystal Microbalance (QCM) 26 5. Steric Stabilisation of Lipid Aggregates 28 5.1.1 Steric Stabilisation of Liposomes 28 5.1.2 Steric Stabilisation by PEG-lipids: Aggregate Structure 30 5.1.3 Steric Stabilisation by PEG-lipids: Permeability Effects 33 5.1.4 Steric Stabilisation by PEG-lipids: Effects on the Interaction between Liposomes and Nonionic Surfactants 37 5.1.5 Other Approaches toward Steric Stabilisation of Liposomes 41 5.1.6 Adsorption of a (PEO)(PPO)(PEO) Triblock Copolymer on SUVs 45 5.2 PEG-lipids as Stabilisers of Aggregates of Dispersed Inverted Phase Lipid 49 5.3 PEG-lipid Micelles 52 6. Liposomes in Drug Delivery 57 6.1 Optimum Lipid Composition 57 6.2 Liposomes Loaded with Boron-containing Compounds Intended for Boron Neutron Capture Therapy (BNCT) 58 6.3 Receptor Targeted Liposomes: Future Work 62 Acknowledgement 64 References 65 1. Introduction The molecules under study in the present thesis are typically found in such diverse locations as cell membranes, soaps and foodstuffs. In general terms they are called amphiphilic molecules, alluding to their unique properties when dissolved in water or oil. To understand the importance of amphiphilic molecules for all forms of life as well as for our everyday life, it is illuminating to consider the function of the molecules in a cell membrane. The living cell is extremely complex and contains, among other things, the genetic code (DNA). It is intuitively realised that for life to exist there must be a barrier that hinders the content of the cell from diffusing into the surrounding medium. Living organisms have solved this problem by surrounding the cell with a semi-permeable barrier, the cell membrane. This membrane is constructed by amphiphilic molecules that have parts that are soluble in water and parts that are soluble in oil. Given the choice, these molecules will assemble such that the water-soluble (polar) parts are directed toward the water medium and the parts that dislike water (apolar) are dissolved in an oil medium. In the case of the cell membrane, the oil medium is represented by the apolar parts of the amphiphilic molecules. In this way, the molecules will build up the cell membrane that regulates everything that passes in or out of the cell. Generally speaking, amphiphilic molecules function in the same way regardless of their location, that is, they assemble at interfaces between polar and apolar media. This is a consequence of their “dual-personality”, having both polar and apolar parts. Because of their preference for interfaces, amphiphilic molecules are often referred to as surfactants (surface-active-agents). When added to aqueous solutions, surfactant molecules may self-assemble into a variety of structures. The basic driving force that brings the molecules together originates from the unfavourable contact between the apolar parts and water [1]. For this reason, the apolar part of the surfactant is often called the hydrophobic part. Indeed, everybody who has tried to mix, for example, olive oil and water recognises this unfavourable interaction. We all know that the oil droplets will not dissolve. The simplest surfactant aggregates are so- called spherical micelles which can be viewed as small spheres having the apolar part of the molecules hidden from water in a core while the polar part of the surfactant is directed outwards against the water medium. A number of other types of surfactant aggregates of larger complexity than the micelle may form, depending on the nature of the surfactant. A brief
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