Design, synthesis and evaluation of multimodal paramagnetic lipids for liposomal fluorescence and magnetic resonance imaging

Molecular imaging techniques have revolutionised our understanding of disease states and the underlying processes causing their occurrence. Such a feat would not have been accomplished without the utilisation of the imaging probes central to the field of molecular imaging. The work undertaken in this thesis describes the synthesis and biological evaluation of lipidic contrast agent probes, designed for effective cellular entry and solid tumour imaging. A gadolinium (Gd) based paramagnetic lipid (Gd.DOTA.DSA) was synthesised and liposome formulations containing this lipid were optimised for maximum cellular labelling. MRI signal enhancing properties of bimodal paramagnetic-fluorescent liposomes utilising Gd.DOTA.DSA was shown both in vitro and in vivo. Tumour MRI results revealed these liposomes to benefit from a prolonged in vivo circulation time and excellent tumour accumulation properties as co-validated by both MRI and fluorescence microscopy of tumour sections. Here, the enhanced permeation and retention (EPR) effect of tumour tissue was exploited, whereby nanoparticles such as the paramagnetic liposomes described, are able to accumulate in tumour tissue due to leaky endothelial layers of damaged blood vessels. A further bimodal fluorescent and paramagnetic lipid (Gd.DOTA.Rhoda.DSA) was designed and synthesised and was shown to label cancer cells in vitro and effectively enhance tumour MRI signal in vivo. These results were also analysed by MRI and fluorescence modalities. Work towards a trimodal fluorescent, 1H and 19F MRI agent was undertaken and prospective routes for its final synthesis purposed

Bioinspired Heparin Nanosponge Prepared by Photo-crosslinking for Controlled Release of Growth Factors

Indexación: Scopus.Growth factors have great therapeutic potential for various disease therapy and tissue engineering applications. However, their clinical efficacy is hampered by low bioavailability, rapid degradation in vivo and non-specific biodistribution. Nanoparticle based delivery systems are being evaluated to overcome these limitations. Herein, we have developed a thermosensitive heparin nanosponge (Hep-NS) by a one step photopolymerization reaction between diacrylated pluronic and thiolated heparin molecules. The amount of heparin in Hep-NS was precisely controlled by varying the heparin amount in the reaction feed. Hep-NS with varying amounts of heparin showed similar size and shape properties, though surface charge decreased with an increase in the amount of heparin conjugation. The anticoagulant activity of the Hep-NS decreased by 65% compared to free heparin, however the Hep-NS retained their growth factor binding ability. Four different growth factors, bFGF, VEGF, BMP-2, and HGF were successfully encapsulated into Hep-NS. In vitro studies showed sustained release of all the growth factors for almost 60 days and the rate of release was directly dependent on the amount of heparin in Hep-NS. The released growth factors retained their bioactivity as assessed by a cell proliferation assay. This heparin nanosponge is therefore a promising nanocarrier for the loading and controlled release of growth factors.https://www.nature.com/articles/s41598-017-14040-5.pd

Cancer nanotechnology: The impact of passive and active targeting in the era of modern cancer biology

Cancer nanotherapeutics are progressing at a steady rate; research and development in the field has experienced an exponential growth since early 2000’s. The path to the commercialization of oncology drugs is long and carries significant risk; however, there is considerable excitement that nanoparticle technologies may contribute to the success of cancer drug development. The pace at which pharmaceutical companies have formed partnerships to use proprietary nanoparticle technologies has considerably accelerated. It is now recognized that by enhancing the efficacy and/or tolerability of new drug candidates, nanotechnology can meaningfully contribute to create differentiated products and improve clinical outcome. This review describes the lessons learned since the commercialization of the first-generation nanomedicines including DOXIL® and Abraxane®. It explores our current understanding of targeted and non-targeted nanoparticles that are under various stages of development, including BIND-014 and MM-398. It highlights the opportunities and challenges faced by nanomedicines in contemporary oncology, where personalized medicine is increasingly the mainstay of cancer therapy. We revisit the fundamental concepts of enhanced permeability and retention effect (EPR) and explore the mechanisms proposed to enhance preferential “retention” in the tumor, whether using active targeting of nanoparticles, binding of drugs to their tumoral targets or the presence of tumor associated macrophages. The overall objective of this review is to enhance our understanding in the design and development of therapeutic nanoparticles for treatment of cancers

A Solvent-Free Thermosponge Nanoparticle Platform for Efficient Delivery of Labile Proteins

Protein therapeutics have gained attention recently for treatment of a myriad of human diseases due to their high potency and unique mechanisms of action. We present the development of a novel polymeric thermosponge nanoparticle for efficient delivery of labile proteins using a solvent-free polymer thermo-expansion mechanism with clinical potential, capable of effectively delivering a range of therapeutic proteins in a sustained manner with no loss of bioactivity, with improved biological half-lives and efficacy in vivo