Table 1.
Examples of vascular nanotherapies in development.
| Therapeutic agent | Nanoparticle | Delivery | Model | In vivo findings | Reference |
|---|---|---|---|---|---|
| Resolving inflammation and defective efferocytosis | |||||
| Annexin A1 mimetic peptide | Type IV collagen-targeted copolymers of PLGA-PEG | Systemic | Ldlr −/− mice | ↓: plaque area, necrotic core, lesional oxidative stress ↑: fibrous cap thickness |
16 |
| IL-10 | Type IV collagen-targeted copolymers of PLGA-PEG | Systemic | Ldlr −/− mice | ↓: necrotic core and lesional oxidative stress ↑: lesional efferocytosis, fibrous cap thickness |
17 |
| Superoxide dismutase mimetic agent and hydrogen-peroxide-eliminating compound | Cyclodextrin-based polysaccharide | Systemic | apoE −/− mice | ↓: ROS-induced inflammation, lesional cholesterol crystals, necrotic core | 18 |
| Prednisolone* | MRI detectable liposomes | Systemic | Hypercholesterolemic rabbits with repeated balloon aortic injury | ↓: plaque inflammation, lesional macrophage content Delivery visualized by MRI Anti-inflammatory effect validated by 18F-FDG/PET-CT and MRI |
19 |
| VCAM1, ICAM1 and 2, E- and P-selectin siRNA | PEI polymer | Systemic | Coronary ligation of apoE −/− mice | ↓: post-myocardial infarction leukocyte recruitment, plaque inflammation, necrotic core, lesion size ↑: fibrous cap thickness |
23 |
| Preventing plaque neovascularization | |||||
| Fumagillin* | avb3 integrin–targeted paramagnetic NPs | Systemic | Hypercholesterolemic rabbits | ↓: aortic plaque angiogenesis, expansion of the vasa vasorum Aortic neovascular delivery and treatment response assessed by MRI |
32 |
| Fumagillin* | avb3 integrin–targeted paramagnetic NPs | Systemic NP delivery, followed by oral statin treatment | Hypercholesterolemic rabbits | Marked anti-angiogenic effect of NPs sustained by statin therapy Angiogenesis of aortic wall assessed by MRI |
33 |
| Targeting macrophages | |||||
| Pitavastatin | PLGA | Systemic | angiotensin II-infused apoE −/− mice | ↓: plaque monocyte infiltration ↑: plaque stability and protection from rupture |
37 |
| CCR2 siRNA* | Lipid NPs | Systemic | apoE −/− mice | ↓: monocyte migration and accumulation, lesion size Changes in biodistribution over time evaluated by FMT-CT |
38 |
| Simvastatin* | Reconstituted HDL | Systemic | apoE −/− mice | ↓: lesion area due to reduced plaque macrophage content, mRNA expression levels of monocyte recruitment and pro-inflammatory genes No effect on serum lipid levels Biodistribution evaluated by ex vivo NIRF Plaque macrophage targeting and treatment efficacy assessed by MRI and FMT/CT |
40 |
| Simvastatin* | Reconstituted HDL | Short-term systemic NP delivery, followed by long-term oral statin treatment | apoE −/− mice | ↓: plaque macrophage proliferation and subsequent plaque inflammation Rapid suppression of inflammation by NP intervention, with sustained effects by oral statin therapy Treatment efficacy assessed by MRI and ex vivo NIRF |
41 |
| Liver X receptor agonist | Type IV collaged-targeted PLA-PEG NPs | Systemic | Ldlr −/− mice | ↓: plaque macrophage content and cholesterol efflux No change in plasma lipid levels and hepatic lipid metabolism |
42 |
| Macrophage scavenger receptor-blocking sugars | Amphiphilic NPs with PEG core | Systemic | apoE −/− mice | ↓: oxidized LDL uptake by macrophages, lipid burden, and overall plaque development | 43 |
| Pioglitazone | PLGA | Systemic | angiotensin II-infused apoE −/− mice | ↓: peripheral inflammatory monocytes, aortic M1 macrophage polarization, plaque rupture ↑: plaque stabilization No effect on plaque macrophage content or lesion area |
44 |
| TRAF6 inhibitor | Reconstituted HDL | Systemic | apoE −/− mice Cynomolgus monkeys |
↓: monocyte recruitment, plaque macrophage content Lack of immune suppressive side effects Liver and spleen accumulation demonstrated by PET/MRI Short-term safety in mice and non-human primates |
39, 45 |
| Near-infrared fluorophore* | Light-activated iron-oxide NPs | Systemic, with local photodynamic therapy | apoE −/− mice | ↓: lesional macrophage content following local light therapy ↑: plaque macrophage apoptosis Plaque localization demonstrated by intravital fluorescence microscopy |
48 |
| Photothermal ablation* | Single-walled carbon nanotubes | Systemic, with local activation by photoluminescence | Mice carotid artery ligation |
In vivo delivery visualized by FMT Ex vivo near-infrared imaging and photothermal ablation of vascular macrophages |
49 |
| Altering lipid metabolism | |||||
| apoB siRNA | Liposomes | Systemic | Cynomolgus monkeys | ↓: apoB mRNA expression in the liver, serum cholesterol, and LDL levels sustained for 11 days following single dose | 52 |
| apoB siRNA | Liposomes | Systemic | Ldlr CETP +/− mice | ↓: apoB protein expression in the liver and serum LDL levels sustained for 3 weeks following single dose | 53 |
| PCSK9 siRNA | Lipidoid-PEG formulation | Systemic | Wild-type mice, rats, cynomolgus monkeys | ↓: plasma PCKS9 protein and LDL levels sustained for 3 weeks following single bolus | 55 |
| TRPV1 antibodies* | Copper sulfide NPs | Systemic, with local photothermal activation | apoE −/− mice | ↓: plaque lipid storage, VSMC foam cell formation, lesion formation ↑: autophagy and cholesterol efflux Vessel delivery monitored by photoacoustic imaging |
61 |
| Preventing neointimal growth | |||||
| Rapamycin | Albumin NPs | Local catheter delivery | Porcine femoral artery balloon injury | ↓: luminal stenosis at 28 days | 64 |
| Rapamycin* | avb3-targeted paramagnetic NPs | Local catheter delivery | Rabbit femoral artery balloon injury | ↓: vascular stenosis, neointimal formation at 14 days No delay in endothelial healing Intramural delivery and luminal changes assessed by MRI |
65 |
| NOX2 siRNA | Lysine-based NPs | Open delivery onto adventitia | Rat carotid artery balloon injury | ↓: ROS production, neointima formation at 14 days | 66 |
| Nitric oxide | Liposomes | Local catheter delivery | Rabbit carotid artery balloon injury | ↓: neointimal proliferation at 14 days | 67 |
| Paclitaxel | Stent-targeted magnetic NPs | Local delivery, with targeting by magnetic exposure | Rat carotid artery stenting | ↓: in-stent neointimal growth at 14 days | 68 |
| Imatinib (PDGF tyrosine kinase inhibitor) | PLGA NP-eluting stents | Coated on stent | Porcine coronary artery stenting | ↓: in-stent restenosis at 28 days No effect on endothelial proliferation |
70 |
| Pitavastatin | PLGA NP-eluting stents | Coated on stent | Porcine coronary artery stenting | ↓: in-stent restenosis at 28 days Lack of delay in endothelial healing |
71 |
| Paclitaxel | Albumin NPs | Systemic | Rabbit iliac artery stenting | ↓: in-stent neointimal growth sustained for 28 days ↑: endothelialization and healing |
74 |
| Paclitaxel | Type IV collagen-targeted lipid-polymeric NPs | Systemic | Rat carotid artery balloon injury | ↓: neointimal proliferation at 14 days | 75 |
| Alendronate (bisphosphonate) | Liposomes | Systemic | Rabbit iliac artery stenting | ↓: blood monocyte count, arterial macrophage infiltration, in-stent neointimal formation at 28 days | 76 |
| Nitric oxide | Nanofibers | Systemic | Rat carotid artery balloon injury | ↓: neointimal hyperplasia sustained for 7 months | 78 |
| Prednisolone | Subendothelial-targeted liposomes | Systemic | Rabbit iliac artery stenting | ↓: in-stent stenosis at 42 days | 79 |
| Targeting thrombosis | |||||
| tPA | PAA-coated iron oxide magnetic NPs | Local catheter delivery, with magnetic targeted thrombolysis | Rat iliac artery embolus | ↑: aortoiliac blood flow, hind limb perfusion | 80 |
| tPA | vWF-targeted gelatin NP complex | Systemic, with drug release enhanced by local ultrasound | Porcine myocardial infarction | ↑: coronary recanalization and left ventricular ejection fraction compared to free tPA | 81 |
| tPA* | Iron oxide PLGA NPs | Systemic | Rat aorta thrombosis | ↑: thrombolytic efficiency Thrombus targeting and thrombolytic activity assessed by MRI |
82 |
| Streptokinase | GPIIb/IIIa and P-selectin-targeted liposomes | Systemic | Mouse carotid artery thrombosis | ↑: delay in thrombus growth, time to vessel occlusion Minimal effect on tail bleeding time Targeting to activated platelets demonstrated by intravital microscopy |
83 |
| Urokinase | Iron oxide magnetic NPs | Local catheter delivery, with magnetic targeted thrombolysis | Rat carotid artery and jugular vein thrombosis | ↑: thrombus dissolution Minimal changes in systemic plasminogen activity and tail bleeding time |
85 |
| Thrombin inhibitor* | PFC NPs | Systemic | apoE −/− mice carotid artery injury | ↓: thrombin-induced inflammatory and pro-coagulant molecules ↑: time to carotid occlusion, restoration of endothelium No change in activated partial thromboplastin time Ex vivo assessment of delivery and endothelial damage by magnetic resonance spectroscopy |
87 |
*
Nanoparticles designed as theranostic agents.
PLGA: poly lactide-co-glycolide. PEG: polyethylene glycol. IL-10: interleukin-10. ROS: reactive oxygen species. VCAM1: vascular cell adhesion molecule 1. ICAM1: intercellular adhesion molecule 1. PEI: polyethyleneimine. MRI: magnetic resonance imaging. 18F-FDG/PET-CT: 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography-computed tomography. PLA: polylactic acid. LDL: low density lipoprotein. HDL: high density lipoprotein. NIRF: near-infrared fluorescence. FMT-CT: fluorescence molecular tomography-computed tomography. CCR2: C-C chemokine receptor type 2. TRAF6: tumor necrosis factor receptor-associated factor 6. apoB: apolipoprotein B. PCSK9: proprotein convertase subtilisin/kexin type 9. TRPV1: transient receptor potential cation channel subfamily V member 1. VSMC: vascular smooth muscle cell. NOX2: NADPH oxidase 2. PDGF: platelet-derived growth factor. GPIIb/IIIa: glycoprotein IIb/IIIa. vWF: von Willebrand factor. tPA: tissue plasminogen activator. PFC: perfluorocarbon.