title: Incorporation of paramagnetic, fluorescent and PET/SPECT contrast agents into liposomes for multimodal imaging.
abstract: A series of metal-chelating lipid conjugates has been designed and synthesized. Each member of the series bears a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) macrocycle attached to the lipid head group, using short n-ethylene glycol (n-EG) spacers of varying length. Liposomes incorporating these lipids, chelated to Gd(3+), (64)Cu(2+), or (111)In(3+), and also incorporating fluorescent lipids, have been prepared, and their application in optical, magnetic resonance (MR) and single-photon emission tomography (SPECT) imaging of cellular uptake and distribution investigated in vitro and in vivo. We have shown that these multimodal liposomes can be used as functional MR contrast agents as well as radionuclide tracers for SPECT, and that they can be optimized for each application. When shielded liposomes were formulated incorporating 50% of a lipid with a short n-EG spacer, to give nanoparticles with a shallow but even coverage of n-EG, they showed good cellular internalization in a range of tumour cells, compared to the limited cellular uptake of conventional shielded liposomes formulated with 7% 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethyleneglycol)(2000)] (DSPE-PEG2000). Moreover, by matching the depth of n-EG coverage to the length of the n-EG spacers of the DOTA lipids, we have shown that similar distributions and blood half lives to DSPE-PEG2000-stabilized liposomes can be achieved. The ability to tune the imaging properties and distribution of these liposomes allows for the future development of a flexible tri-modal imaging agent.
authors.affiliation: Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon St, London WC1H 0AJ, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Mitchell
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Kalber
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Cooper
authors.forename: Kavitha
authors.initials: K
authors.lastname: Sunassee
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Chalker
authors.forename: Karen P
authors.initials: KP
authors.lastname: Shaw
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Ordidge
authors.forename: Adam
authors.initials: A
authors.lastname: Badar
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Janes
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Blower
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.forename: Helen C
authors.initials: HC
authors.lastname: Hailes
authors.forename: Alethea B
authors.initials: AB
authors.lastname: Tabor
mesh_terms: D003287:Contrast Media / Q000138:chemical synthesis*; D008081:Liposomes / Q000737:chemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008856:Microscopy, Fluorescence / Q000379:methods*; D053769:Nanocapsules / Q000737:chemistry*; D013382:Subtraction Technique; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D003287:Contrast Media; D008081:Liposomes; D053769:Nanocapsules