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Lipid conjugates for nanoparticle delivery
We have been investigating the structural requirements for lipids in a range of nanoparticles including ternary delivery systems comprised of a lipid (L), targeting peptide (P) and DNA or RNA (D or R). This work has been carried out with Prof. A. B. Tabor and collaborators at King’s College London/Manchester (Prof M. J. Lawrence). The ternary LPD lipopolyplex systems have displayed high transfection efficiencies and low toxicity in vitro and in vivo, transfected non-dividing cells efficiently, and were well tolerated with low immunogenicity in vivo. Issues related to vector efficacy were tackled including targeting accessibility and the influence of the structure of the lipid on particle stability and delivery. In addition, activities included: - The design and synthesis of several series of novel lipids, which enhance transfection efficacy due to better particle stability. The structure and fate of the nanoparticles formed was studied using confocal microscopy via the synthesis of specifically labelled lipids. - For in vivo applications, as well as incorporating PEG linkers to aid particle stability, cleavable moieties were also introduced into the lipids to enhance release from the endosome. -Trichain lipids have also recently been developed with enhance delivery properties. As part of the multidisciplinary "KCL and UCL Cancer Imaging Centre" funded via the CRUK and EPSRC with Prof T. Ng (PI) and other collaborators we have developed new strategies for in vivo cancer imaging. Liposomal delivery formed part of one investigative theme. Here we synthesized a series of metal-chelating lipid conjugates as multimodal liposomes for use as functional MR contrast agents as well as radionuclide tracers for SPECT. These were combined with shielding lipids and tuned for in vivo applications.
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