Nanoparticle-based delivery of simvastatin inhibits plaque macrophage proliferation in apolipoprotein E–deficient mice.
Nanoparticle applications in medicine have seen a tremendous growth in the last decade. In addition to their drug targeting application and their ability to improve bioavailability of drugs, nanoparticles can be designed to allow their detection with a variety of imaging methodologies. In the current study we developed a multimodal nanoparticle platform to enable imaging guided therapy, which was evaluated in a colon cancer mouse model. This “theranostic” platform, is based on oil-in-water nanoemulsions and carries iron oxide nanocrystals for MRI, the fluorescent dye Cy7 for NIRF imaging and the hydrophobic glucocorticoid prednisolone acetate valerate (PAV) for therapeutic purposes. Angiogenesis targeted nanoemulsions functionalized with αvβ3-specific RGD-peptides were evaluated as well. When subcutaneous tumor were palpable the nanoemulsions were administered at a dose of 30 mg FeO/kg and 10 mg PAV/kg. MRI and NIRF imaging showed significant nanoparticle accumulation in the tumors, while tumor growth profiles revealed a potent inhibitory effect in all the PAV-nanoemulsions treated animals as compared to the ones treated with control nanoemulsions, the free drug or saline. In conclusion, this study demonstrated that our nanoemulsions, when loaded with PAV, iron oxide nanocrystals and Cy7, represent a flexible and unique theranostic nanoparticle platform that can be applied for imaging guided therapy of cancer.
Atherosclerosis is a major cause of global morbidity and mortality that could benefit from novel targeted therapeutics. Recent studies have shown efficient and local drug delivery with nanoparticles, although the nanoparticle targeting mechanism for atherosclerosis has not yet been fully elucidated. Here we used in vivo and ex vivo multimodal imaging to examine permeability of the vessel wall and atherosclerotic plaque accumulation of fluorescently labeled liposomal nanoparticles in a rabbit model. We found a strong correlation between permeability as established by in vivo dynamic contrast enhanced magnetic resonance imaging and nanoparticle plaque accumulation with subsequent nanoparticle distribution throughout the vessel wall. These key observations will enable the development of nanotherapeutic strategies for atherosclerosis.
Objectives Our aim was to develop and validate a non-invasive imaging tool to visualize HDL’s in vivo behavior by positron emission tomography (PET), with an emphasis on its plaque targeting abilities. Background High-density lipoprotein (HDL) is a natural nanoparticle that interacts with atherosclerotic plaque macrophages to facilitate reverse cholesterol transport. HDL-cholesterol concentration in blood is inversely associated with risk of coronary heart disease and remains one of the strongest independent predictors of incident cardiovascular events. Methods Discoidal HDL nanoparticles were prepared by reconstitution of its components apolipoprotein A-I (APOA1) and the phospholipid DMPC. For radiolabeling with Zirconium-89 (89Zr), the chelator DFO was introduced by conjugation to APOA1 or as a phospholipid-chelator (DSPE-DFO). Radiolabeled HDL’s biodistribution and plaque targeting was studied in established murine, rabbit and porcine atherosclerosis models by PET combined with computed tomography (PET/CT) or with magnetic resonance imaging (PET/MRI). Ex vivo validation was conducted by radioactivity counting, autoradiography and near infrared fluorescence imaging. Flow cytometric assessment of cellular specificity in different tissues was performed in the murine model. Results We observed distinct pharmacokinetic profiles for the two 89Zr-HDL nanoparticles. Both APOA1- and phospholipid-labeled HDL mainly accumulated in kidneys, liver and spleen with some marked quantitative differences in radioactivity uptake values. Radioactivity concentrations in rabbit atherosclerotic aortas were 3–4-fold higher than in controls at 5 days p.i. for both 89Zr-HDL nanoparticles. In the porcine model, we observed increased accumulation of radioactivity in lesions by in vivo PET imaging. Irrespective of the radiolabel’s location we found HDL nanoparticles to preferentially target plaque macrophages and monocytes. Conclusions 89Zr labeling of HDL allows studying its in vivo behavior by non-invasive PET imaging, including visualization of its accumulation in advanced atherosclerotic lesions. The different labeling strategies provide insight on the pharmacokinetics and biodistribution of HDL’s main components, i.e. phospholipids and APOA1.
Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents’ risk–benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP’s liposomal encapsulation improved its pharmacokinetic profile in humans (n = 13) as attested by an increased plasma half-life of 63 h (LN-PLP 1.5 mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n = 14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n = 30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis.
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