Stabilization of liposomal functional anchors by cross-linkable lipids

Micro- and nanoparticles are designed to deliver drugs and contrast agents to their target site in a controlled manner. One of the greatest obstacles in the performance of such delivery vehicles is their stability in the presence of serum. Here we investigate a method to stabilize a class of liposomes in which lipid vesicles are modified post- fabrication through surface adsorption and anchoring. We hypothesized that the sequential adsorption of functional units followed by covalent cross-linking of the liposome would provide enhanced stability in the presence of human serum. To investigate this hypothesis, liposomes composed of diyne-containing lipids were assembled and functionalized via chitosan conjugated with a hydrophobic anchor and the magnetic resonance (MR) contrast agent, gadolinium, as a model functionality. This strategy served to stabilize the thermodynamically favorable association between liposome and modified functional chitosan. Furthermore, the chitosan-coated, cross-linked liposomes proved more effective as delivery vehicles of MR contrast agents than uncross-linked liposomes due to the reduced liposome degradation and chitosan desorption. Overall, this study demonstrates a useful method to stabilize a broad class of particles used for systemic delivery of various molecular cargos

Polymer-mediated assembly of MRI contrast agents and their use in imaging of vascular defects

Defective, leaky vasculature is characteristic of a wide variety of diseases, including arthritis, cancer, and cardiovascular disease. The ability to locally highlight vascular defects via medical imaging may therefore provide a way to improve diagnosis and treatment of some of the most significant diseases worldwide. As magnetic resonance imaging (MRI) provides the highest spatial resolution and best soft tissue contrast among common imaging techniques, it remains an appealing approach to vascular imaging. MRI, however, has relatively low sensitivity to its contrast agents compared to other clinical modalities, which limits its use in targeted applications. To address this issue, this thesis investigates the use of polymer materials to control the size, morphology, spatial organization, and surface properties of MR imaging probes to improve their relaxivity and accumulation at sites of interest. The first part of this thesis focuses on the design and development of gadolinium-based contrast agents. Chapter 2 describes the synthesis of a polymeric fastener to anchor gadolinium to the surface of a liposome through electrostatic and hydrophobic interactions. As a result, the probe provided greater contrast per dose than gadolinium chelates used clinically, and was able to beacon areas of vascular damage in in vivo models of ischemia. The strategy was then adapted to rapidly label stem cells for applications in cell tracking, as described in Chapter 3. Secondly, methods to improve the in vivo performance of superparamagnetic iron oxide nanoparticle (SPION) contrast agents are investigated. Chapter 4 explores the use of hyperbranched polyglycerol (HPG) in assembling SPIONs in the form of spherical clusters. By controlling the cluster size and molecular architecture of the polymer coating, optimal relaxivity of the SPIONs was achieved for sensitive imaging. In Chapter 5, the SPION clusters are further improved with the incorporation of targeting ligands and by inducing a wormlike morphology. This allowed for greater accumulation in areas of defective vasculature. Overall, this work contributes to a better understanding of contrast agent design and may serve to expedite efforts to improve the diagnosis and treatment of vascular diseases

Stabilization of liposomal functional anchors by cross-linkable lipids

Micro- and nanoparticles are designed to deliver drugs and contrast agents to their target site in a controlled manner. One of the greatest obstacles in the performance of such delivery vehicles is their stability in the presence of serum. Here we investigate a method to stabilize a class of liposomes in which lipid vesicles are modified post- fabrication through surface adsorption and anchoring. We hypothesized that the sequential adsorption of functional units followed by covalent cross-linking of the liposome would provide enhanced stability in the presence of human serum. To investigate this hypothesis, liposomes composed of diyne-containing lipids were assembled and functionalized via chitosan conjugated with a hydrophobic anchor and the magnetic resonance (MR) contrast agent, gadolinium, as a model functionality. This strategy served to stabilize the thermodynamically favorable association between liposome and modified functional chitosan. Furthermore, the chitosan-coated, cross-linked liposomes proved more effective as delivery vehicles of MR contrast agents than uncross-linked liposomes due to the reduced liposome degradation and chitosan desorption. Overall, this study demonstrates a useful method to stabilize a broad class of particles used for systemic delivery of various molecular cargos.LimitedAuthor requested closed access (OA after 2yrs) in Vireo ETD syste

Cross-Linkable Liposomes Stabilize a Magnetic Resonance Contrast-Enhancing Polymeric Fastener

Liposomes are commonly used to deliver drugs and contrast agents to their target site in a controlled manner. One of the greatest obstacles in the performance of such delivery vehicles is their stability in the presence of serum. Here, we demonstrate a method to stabilize a class of liposomes that load gadolinium, a magnetic resonance (MR) contrast agent, as a model cargo on their surfaces. We hypothesized that the sequential adsorption of a gadolinium-binding chitosan fastener on the liposome surface followed by covalent cross-linking of the lipid bilayer would provide enhanced stability and improved MR signal in the presence of human serum. To investigate this hypothesis, liposomes composed of diyne-containing lipids were assembled and functionalized via chitosan conjugated with a hydrophobic anchor and diethylenetriaminepentaacetic acid (DTPA). This postadsorption cross-linking strategy served to stabilize the thermodynamically favorable association between liposome and polymeric fastener. Furthermore, the chitosan-coated, cross-linked liposomes proved more effective as delivery vehicles of gadolinium than uncross-linked liposomes due to the reduced liposome degradation and chitosan desorption. Overall, this study demonstrates a useful method to stabilize a broad class of particles used for systemic delivery of various molecular payloads

Making changes to assessment methods in social work education: focusing on process and outcome

Moving towards delivering the new social work qualification led to many social work programmes considering the 'fitness for purpose' of assessment methods being used to assess the competence of social work students. This article highlights how changes in assessment methods were considered on one particular social work programme. The advantages and disadvantages of three particular assessment methods in relation to professional practice are debated here. Discussions emanating from these considerations and subsequent changes made to the programme are highlighted. The specific focus is on the experience of one particular social work programme which is used as a case study to illustrate issues of general relevance in social work education. It is intended that the reflections presented in this article will contribute to this broader arena of learning and teaching for professional practice taking place and continuing beyond the introduction of the new qualification

Tailoring Polymersome Bilayer Permeability Improves Enhanced Permeability and Retention Effect for Bioimaging

Self-assembled nanoparticles conjugated with various imaging contrast agents have been used for the detection and imaging of pathologic tissues. Inadvertently, these nanoparticles undergo fast, dilution-induced disintegration in circulation and quickly lose their capability to associate with and image the site of interest. To resolve this challenge, we hypothesize that decreasing the bilayer permeability of polymersomes can stabilize their structure, extend their lifetime in circulation, and hence improve the quality of bioimaging when the polymersome is coupled with an imaging probe. This hypothesis is examined by using poly­(2-hydroxyethyl-<i>co</i>-octadecyl aspartamide), sequentially modified with methacrylate groups, to build model polymersomes. The bilayer permeability of the polymersome is decreased by increasing the packing density of the bilayer with methacrylate groups and is further decreased by inducing chemical cross-linking reactions between the methacrylate groups. The polymersome with decreased bilayer permeability demonstrates greater particle stability in physiological media and ultimately can better highlight tumors in mice over 2 days compared to those with higher bilayer permeability after labeling with a near-infrared (NIR) fluorescent probe. We envisage that the resulting nanoparticles will not only improve diagnosis but also further image-guided therapies

Flow-Mediated Stem Cell Labeling with Superparamagnetic Iron Oxide Nanoparticle Clusters

This study presents a strategy to enhance the uptake of superparamagnetic iron oxide nanoparticle (SPIO) clusters by manipulating the cellular mechanical environment. Specifically, stem cells exposed to an orbital flow ingested almost a 2-fold greater amount of SPIO clusters than those cultured statically. Improvements in magnetic resonance (MR) contrast were subsequently achieved for labeled cells in collagen gels and a mouse model. Overall, this strategy will serve to improve the efficiency of cell tracking and therapies

A Polymeric Fastener Can Easily Functionalize Liposome Surfaces with Gadolinium for Enhanced Magnetic Resonance Imaging

Common methods of loading magnetic resonance imaging (MRI) contrast agents into nanoparticles often suffer from challenges related to particle formation, complex chemical modification/purification steps, and reduced contrast efficiency. This study presents a simple, yet advanced process to address these issues by loading gadolinium, an MRI contrast agent, exclusively on a liposome surface using a polymeric fastener. The fastener, so named for its ability to physically link the two functional components together, consisted of chitosan substituted with diethylenetriaminepentaacetic acid (DTPA) to chelate gadolinium, as well as octadecyl chains to stabilize the modified chitosan on the liposome surface. The assembly strategy, mimicking the mechanisms by which viruses and proteins naturally anchor to a cell, provided greater <i>T</i>₁ relaxivity than liposomes loaded with gadolinium in both the interior and outer leaflet. Gadolinium-coated liposomes were ultimately evaluated <i>in vivo</i> using murine ischemia models to highlight the diagnostic capability of the system. Taken together, this process decouples particle assembly and functionalization and, therefore, has considerable potential to enhance imaging quality while alleviating many of the difficulties associated with multifunctional particle fabrication