Thrombus-specific manganese-based “nanobialys” for MR molecular imaging of ruptured plaque
Journal of Cardiovascular Magnetic Resonance volume 14, Article number: P136 (2012)
Mathematical modeling studies have suggested that nonspherical, disc-shaped nanoparticles may have optimal intravascular flow and homing characteristics. In this study, we report the development of a fibrin-specific high-relaxivity bialy-shaped polymeric nanoparticle using porphyrin-chelated manganese. We anticipate that this agent would be highly effective for molecular imaging of microthrombi in ruptured atherosclerotic plaques.
Detection of microthrombi within fissures of vulnerable atherosclerotic plaques requires a sensitive molecular imaging contrast agent. Moreover, recent reports based on mathematical modeling suggest that nonspherical, disc-shaped nanoparticles could have improved intravascular flow characteristics, which may improve ligand-directed targeting. In light of the concern surrounding the use of gadolinium in patients with severe renal disease, the goal of this research was to develop a nonspherical fibrin-targeted manganese-based molecular imaging agent.
A new class of manganese (III)-labeled, a toroidal-shaped, vascularly-constrained nanoparticles, “nano-bialys (MnNBs)”, was designed, synthesized, physically characterized, and evaluated for MR properties. Single slice inversion recovery and multi-echo spin echo sequences were used to calculate the ionic (per metal) and particulate (per particle) relaxivities from 7 serial dilutions of nanobialys at 1.5T and 25°C. Fibrin clots supported on silk suture suspended in PBS were targeted with MnNB or control (non-paramagnetic) NB to the fibrin clots with avidin-biotin interactions and fibrin-specific antibodies (NIB5F3). Magnetic resonance images (3T) of the clots were acquired using T1-weighted gradient echo techniques.
Mn-nano-bialys were 190nm ± 5nm with polydispersity of 0.26±0.01. (Fig 1) In the hydrated state, Manganese content was 25.6 ± 03 µg/mL by ICP OES, i.e., 165,000 Mn(III) per nanobialy. The particulate relaxivities of the MnNB were high, r1=612,307±7213 and r2= 866,989±10704 (s●mmol [nanobialy])-1 measured at 1.5T (25°C), with ionic r1 and r2 relaxivities of 3.7±1.1 and 5.2±1.1 (s●mmol [Mn])-1, respectively. MR imaging of MnNB targeted to fibrin clot phantoms showed clear contrast enhancement, while control clots had no (p<0.05) contrast change (Fig 2).
Fibrin-specific MnNBs are a novel, high relaxivity, non-gadolinium, molecular imaging agent that offers a sensitive noninvasive MR imaging approach for diagnosis of ruptured atherosclerotic plaques.
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Pan, D., Caruthers, S.D., SenPan, A. et al. Thrombus-specific manganese-based “nanobialys” for MR molecular imaging of ruptured plaque. J Cardiovasc Magn Reson 14 (Suppl 1), P136 (2012). https://doi.org/10.1186/1532-429X-14-S1-P136