Multifunctional agents for concurrent imaging and therapy in cardiovascular disease

Abstract

The development of agents for the simultaneous detection and treatment of disease has recently gained significant attention. These multifunctional theranostic agents posses a number of advantages over their monofunctional counterparts, as they potentially allow for the concomitant determination of agent localization, release, and efficacy. Whereas the development of these agents for use in cancers has received the majority of the attention, their use in cardiovascular disease is steadily increasing. As such, this review summarized some of the most poignant recent advances in the development of theranostic agents for the treatment of this class of diseases.

Figure 1

MRI of abdominal aorta showing outline of segmented region of interest (ROI) (top), false-colored overlay of percent signal enhancement at time of treatment (middle), and 1 week post-treatment (bottom). The color overlays are thresholded at 10% enhancement to show some anatomic detail within the ROI. Reproduced with permission from [21].

Figure 2

Focal macrophage ablation. In vivo localization of the phototoxic nanoagent to carotid atheroma, as determined by intravital fluorescence microscopy. A) Fluorescence image in the AF750 channel demonstrating particle uptake by a carotid plaque. B) Fluorescence angiogram utilizing fluorescein-labeled dextran outlining the vasculature. C) Merged image of the two fluorescence channels.

Figure 3

Serial histological analysis of femoral arteries 2 weeks after balloon overstretch injury. Top, Treatment with α_νβ₃-integrin–targeted rapamycin nanoparticles. Bottom, Serial sections of injured femoral segment after exposure to α_νβ₃-integrin–targeted nanoparticles without drug. Serial cryosections stained with H&E represent 2-mm segments starting proximal to the injury (left) and ending distally (right). Lesion areas are depicted in green/orange and illustrate an irregular pattern of stenosis development and remodeling response along the injured vessel segments. Reproduced with permission from [35].

Figure 4

Localization of CREKA micelles in atherosclerotic plaques. (A) Serial cross-sections (5 μm thick) were stained with antibodies against CD31 (endothelial cells; Top), CD68 (macrophages and other lymphocytes; Middle), and fibrin(ogen) (Bottom). Representative microscopic fields are shown to illustrate the localization of micelle nanoparticles in the atherosclerotic plaque. Micelles are bound to the entire surface of the plaque with no apparent binding to the healthy portion of the vessel. CREKA targeted micelles also penetrate under the endothelial layer (CD31 staining) in the shoulder of the plaque (Inset) where there is high inflammation (CD68 staining) and the plaque is prone to rupture. Clotted plasma proteins are seen throughout the plaque and its surface [fibrin(ogen) staining]. (Left) Images were taken at a 10× magnification. (Scale bar, 200 μm.) (Right) Images were taken at a 150× magnification. (Scale bar, 20 μm.) (B) Fluorescence was not observed in the heart or lung, and only a small amount was seen in the kidney, spleen, and liver. Images were taken at a 20× magnification. (Scale bar, 100 μm.) Reproduced with permission from [37].

Figure 5

MNP-bound rtPA improved tissue perfusion in a rat embolic model. Hind limb skin tissue perfusion of the rat was measured by a laser Doppler perfusion imager. After clot lodging into the left iliac artery, rtPA (0.2 mg/kg; 0.27 U/kg), MNP-bound rtPA (0.2 mg/kg; 0.22 U/kg) or equivalent MNP (2.5 mg/kg) was administered from the right iliac arterial 5 min after introducing the clot. Reproduced with permission from [49].