Manganese G8 dendrimers targeted to oxidation‐specific epitopes: In vivo MR imaging of atherosclerosis

Abstract

Objective To determine if manganese (Mn) G8 dendrimers targeted to oxidation-specific epitopes (OSE) allow for in vivo detection of atherosclerotic lesions. Background OSE have been identified as key factors in atherosclerotic plaque progression and destabilization. Mn offers a potentially clinically translatable alternative to gadolinium-based agents when bioretention and potential toxicity of gadolinium is anticipated. However, to be effective, high payloads of Mn must accumulate intracellularly in macrophages. It was hypothesized that G8 dendrimers targeted to OSE may allow delivery of high Mn payloads, thereby enabling in vivo detection of macrophage rich plaques. Methods G8 dendrimers were modified to allow conjugation with MnDTPA (758 Mn ion) and the antibody MDA2 that is targeted to malondialdehyde (MDA)-lysine epitopes. Both the untargeted and targeted G8 dendrimers were characterized and their in vivo efficacy evaluated in apoE-/- mice over a 96-hour time period after bolus administration of a 0.05 mmol Mn/kg dose using a clinical MR system (3 Tesla). Results Significant enhancement (normalized enhancement >60%, p=0.0013) of atherosclerotic lesions was observed within a 72-hour time period following administration of the targeted dendrimers. The presence of Mn within atherosclerotic lesions was confirmed using spectroscopic methods (>8 μg Mn/g). Limited signal attenuation (<18%) and Mn deposition (< 1 μg Mn/g) was observed in the arterial wall following injection of the untargeted material. Conclusions This study demonstrates that manganese labeled dendrimers, allowing a high Mn payload, targeted to OSE may allow in vivo image of atherosclerotic lesions.

Imaging of Oxidation-Specific Epitopes with Targeted Nanoparticles to Detect High-Risk Atherosclerotic Lesions: Progress and Future Directions

“…The dendrimers are used to load large amounts of Mn while keeping the particle size small enough (<20 nm) to allow for intra-plaque macrophage uptake. Generation eight dendrimers (G8) contain 1024 primary amine groups that may be modified and labeled with MnDTPA, a significant improvement over the MnDTPA micelles where there are ≈50 MnDTPA per micelle [83]. The hydrodynamic size (diameter) and in vitro R1 values associated with the OSE targeted dendrimers were similar to the values reported for the targeted Mn micelles (13.34 ± 1.2 nm, R1 saline = 3.5 s−1mM−1).…”

Two decades of dendrimers as versatile MRI agents: a tale with and without metals

“…This target is one of the oxidation‐specific epitopes (OSE) that is expressed in atherosclerotic plaques. An enhancement >60% could be observed compared to the untargeted counterpart . Other modalities beyond MRI have been further studied.…”

Nanotechnology in Diagnosis and Treatment of Coronary Artery Disease

“…Dendrimers are more used in cell-labeling rather than in ISR therapy. For instance, manganese G8 dendrimers [48] have been successfully applied in atherosclerosis detection. One study described the development of ‘tadpole’ dendrimeric materials for siRNA delivery in a rat ischemia-reperfusion model.…”