Abstract
Methods 1) P22: The P22 protein cage (60 nm) is bioengineered with an internal polymer network with amine functional groups allowing incorporation of ~9100 Gd-DTPA molecules per cage via the amine groups (Figure 1: [1]). This provides a per cage relaxivity of 70000 mMs, superior to Gd-DTPA for the equivalent Gd concentration. 2) Atherosclerosis Models: Both ApoE-deficient (ApoE) and FVB mice were used. ApoE mice develop atherosclerosis enhanced by high-fat diet. FVB mice develop macrophage-rich carotid lesions with carotid ligation in combination with high-fat diet and diabetes induction [2]. 3) P22-polymer-Gd in vivo MR imaging: Mice were injected intravenously with P22-polymer-Gd (N=5, 20 μmol Gd/kg, one-fifth the typical clinical dose) or Magnevist (N=1, 20 μmol Gd/kg). Vascular MRA at 1T was performed (Aspect M2, 500 mT/m, 2500 T/m/s) using 3D-SPGR (TR/TE=12 ms/2.1 ms, slice thickness=1 mm, FOV=5 cm, matrix=128x128, FA=45). Vessel wall MRI at 3T was performed (Signa HDx, GE Healthcare, 50mT/m, 150 T/m/s) with a phased-array mouse coil (RAPID MR International), using a double inversion recovery fast spin echo sequence (TR/TE= 400 ms/15 ms, slice thickness=1mm, FOV=3 cm, matrix= 256x256) up to 24 hours after injection. 4) RGD-targeted P22 ex vivo fluorescence imaging: Molecular targeting of P22 was evaluated by attaching RGD peptides externally, which targets the aVb3 integrin, upregulated on activated macrophages. ApoE mice (N=4) were injected intravenously with RGDP22 or RGD P22 (labeled with Cy5.5, 4 nmol/mouse). Forty-eight hours later, ex vivo fluorescence imaging was performed using Maestro imaging system (Cri, Woburn, MA). Maximum plaque signal intensities were measured and compared.
Highlights
The bacteriophage P22 protein cage can be bioengineered to contain a high-relaxivity gadolinium (Gd) payload internally and targeting ligands externally
1) P22: The P22 protein cage (60 nm) is bioengineered with an internal polymer network with amine functional groups allowing incorporation of ~9100 Gd-DTPA molecules per cage via the amine groups (Figure 1: [1]). This provides a per cage relaxivity of 70000 mM-1s-1, superior to Gd-DTPA for the equivalent Gd concentration
ApoE-/- mice develop atherosclerosis enhanced by high-fat diet
Summary
High-Gd-Payload P22 protein cage nanoparticles for imaging vascular inflammation. Hisanori Kosuge1*, Masaki Uchida, Janice Lucon, Shefah Qazi, Trevor Douglas, Michael V McConnell. From 16th Annual SCMR Scientific Sessions San Francisco, CA, USA. From 16th Annual SCMR Scientific Sessions San Francisco, CA, USA. 31 January - 3 February 2013
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