Long-circulating liposomes radiolabeled with [18F]fluorodipalmitin ([18F]FDP)

Abstract

Synthesis of a radiolabeled diglyceride 3-[ 18 F]fluorodipalmitoyl-1,2-glycerol ( 18 F-fluorodipalmitin, [ 18 F]FDP) and its potential as a reagent for radiolabeling long-circulating liposomes were investigated. The incorporation of 18 F into the lipid molecule was accomplished by nucleophilic substitution of p-toluenesolfonyl moiety with a decay corrected yield of 43 ± 10% (n = 12). Radiolabeled long-circulating PEG-coated liposomes were prepared using a mixture of DPPC, cholesterol, DSPE-PEG2000 (61:30:9) and [ 18 F]FDP with a decay corrected yield of 70 ± 8% (n = 4). PET imaging and biodistribution studies were performed with free [ 18 Liposomes are vesicles composed of one or more concentric phospholipid bi-layers and such vesicles have been widely investigated as possible drug carriers [1,2]. Prolonged blood circulation of the liposomes is achieved with the addition of a polyethylene glycol (PEG) coating, which efficiently minimizes their removal by macrophages of the reticuloendothelial system [3][4][5][6]. Liposomes with various target-specific ligands attached to their surface are being investigated for targeted drug delivery [1,2,7]. Liposomes labeled with radioisotopes such as 99m Tc, 186 Re, 67 Ga, 111 In, and 18 F were previously employed to study the biodistribution of different types of liposomes in various animal models using scintigraphy, SPECT and PET. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Materials and Methods GeneralThe solvents and chemicals were purchased from Aldrich (Milwaukee, WI). The 1 H and 13 C NMR spectra were recorded using a Bruker Avance 500 spectrometer and the chemical shifts are reported relative to TMS. Analytical reversed-phase HPLC was performed using a Phenomenex Jupiter 5μ C4 300A column ( . The size distribution of liposomes was determined using a particle size analyzer Nanotrac NPA150 purchased from Microtrac Inc. (North Largo, FL). The lipid concentration was determined using a Phospholipids B kit purchased from Wako Chemicals, Inc. (Richmond, VA). Synthesis of 3-tosyl-1,2-dipalmitoyl glycerol (2)The precursor 2 was prepared according to the previously published procedure [32] from 1,2-dipalmitoyl-sn-glycerol (1) and 4-toluenesulfonyl chloride. The crude product was subsequently purified by recrystalization from hexane. 1 mL). The content of the vial was dissolved in anhydrous acetonitrile (0.35 mL) and transferred into a suspension of 2 (5.5 mg) in anhydrous acetonitrile (0.5 mL). The reaction mixture was heated to 100 ºC for 20 minutes and allowed to cool to room temperature for 5 min...

Dynamic imaging of arginine-rich heart-targeted vehicles in a mouse model

“…With the exception of studies involving CRRRR, in all data reported here and in [25], activity in the bladder increased only after a delay of ~1000 seconds. With particles containing CRRRR, activity in the bladder increased immediately after injection of the particles, with this difference hypothesized to result from immediate cellular internalization of these particles or rapid extracellular enzymatic breakdown of the radiolabeled lipid.…”

“…Here, in order to facilitate high-resolution pharmacodynamic measurements, we employ 18 F for PET trafficking of peptide-targeted liposomes (Figure 1), using an 18 [25]. When free lipid is injected or the vehicle is recognized and metabolized by the RES, the 18 F-containing metabolite rapidly clears from the liver, facilitating real-time evaluation of the dynamics [25].…”

“…Here, in order to facilitate high-resolution pharmacodynamic measurements, we employ 18 F for PET trafficking of peptide-targeted liposomes (Figure 1), using an 18 [25]. When free lipid is injected or the vehicle is recognized and metabolized by the RES, the 18 F-containing metabolite rapidly clears from the liver, facilitating real-time evaluation of the dynamics [25]. Other advantages of the [ 18 F]FDP label include the absence of any change in surface properties due to the effects of chelators, the small size of the 18 F group attached to the lipid head group, the simplicity of the labeling, and the generality of the approach.…”

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