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 Gd3+, 64Cu2+, or 111In3+, 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.

Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

“…Dual-mode computed tomography–MRI imaging in rats and mice was achieved using multifunctional Gd-loaded dendrimer-entrapped gold nanoparticles 126 . Simultaneous optical imaging, computed tomography imaging and MRI was made possible using liposomes labelled with a fluorophore tracer, 99m Tc, 111 In or 64 Cu and Gd 127,128 in mouse models. Moreover, the addition of a radionuclide 129 enables the imaging system to become a therapeutic.…”

Lung inflammation does not affect the clearance kinetics of lipid nanocapsules following pulmonary administration

“…Suspensions were diluted to 12 mg/mL with 0.1 M ammonium acetate (pH 6.6) [24]. 111 Indium-chloride (Mallinckrodt Medical Inc, Petten, The Netherlands), ~50 MBq ( 111 InCl 3 , half-life 2.83 days), was dissolved in 0.5 M ammonium acetate (pH 5.0) and mixed with LNC50-DMPE-DTPA at a ratio of 1:2 v/v.…”

Synthesis and application of strawberry-like Fe 3 O 4 -Au nanoparticles as CT-MR dual-modality contrast agents in accurate detection of the progressive liver disease

“…It is attractive to combine imaging modalities that involve different mechanism from data collection to image processing to eliminate weaknesses of individual modality and improve diagnostic accuracy. Recently, reports of potential candidates for dualmodality or more are blooming, including multifunctional contrast agents for CT-MR [24e31], PET-MR [56e58], SPECT-MR [59], SPECT-CT [60], FL-MR [61e63] and so on. Though multimodality contrast agents seem to be a versatile answer to clinical obstacles, several aspects must be considered in future work.…”