Table 3.

Nanoparticle strategies for the delivery of ani inflammatory/chemotherapeutics to the atherosclerotic plaque.

Therapeutic Agent	Nanoparticle	Key nanoparticle materials	Size/Charge	Loading capacity (LC) and loading efficiency (LE)	Route of delivery	Injected dose	Model	Targeting strategy	Key Findings	Reference
Methotrexate (MTX)	Polymeric Nanoparticle	PLGA core stabilised with EGG-PG and DSPE-PEG	100 nm −60 mV	LE = 57.4% LC = 2.8%	IV injection	20 μg of MTX, bi weekly for 4 weeks	ApoE−/− mice	N/A	Reduced plaque burden by 50% in treatment group compared to control group, in high fat diet mice in 1 month.	[110]
Dexamethasone	Liposome	DPPC and PEG-2000-DSPE	100 nm; 5.1±1.4 mV	LC = 0.13 mg dexamethasone phosphate per μmol of phospholipid	–	–	In vitro model using peripheral blood mononuclear cells (PBMC)	N/A	Inhibited migration of monocytes Reduced release of TNFa and IL6 which are proinflammatory cytokines.	[111]
Didodecyl-methotrexate (ddMTX)	Lipid core nanoparticles (LDE)	Lipid mixture (Cholesterol oleate, phosphatidylcholine, triolein and cholesterol)	<220 nm	LC = 0.2 mg/mg NP	IV injection	4 mg/kg of MTX, injected once per week for 4 weeks	Male NZ white rabbits. 1% cholesterol diet- 8wks	LDE is taken up by the cells through the LDL receptor mediated endocytic pathway	65% lesion reduction in LDE-ddMTX compared to control Decrease in gene expression of TNF-α, VCAM-1 IL-1β, MCP-1, IL-18, MMP-9 and MMP-12 in aortic arch of treatment group.	[112]
Paclitaxel	Lipid core nanoparticles (LDE)	Lipid mixture (Cholesterol oleate, phosphatidylcholine, miglyol and cholesterol)	N/A	LC = 60 mg of PTX were added in 606 mg of lipids	Intraperitoneal injection	4 mg/mL, weekly for 4 weeks	LDLR −/− mice	LDE uptake by different mechanism and not through the LDL receptor pathway	Reduction of lesions in wall area (14%) and stenosis (22%) observed by MRI in treatment compared to model	[113]
Paclitaxel	Lipid core nanoparticles (LDE)	Lipid mixture (Cholesterol oleate, phosphatidylcholine, miglyol and cholesterol)	40.69 ± 1.44 nm and 83.61 ± 1.85 nm	LC = 60 mg of PTX were added in 606 mg of lipids	IV injection	4 mg/kg of PTX, injected once per week for 4 weeks	Male NZ white rabbits. 1% cholesterol diet- 8wks	LDE is taken up by the cells through the LDL receptor mediated endocytic pathway	Size of the NPs do not significantly impact the treatment 54–56% decrease in the lesion area of the rabbit aortas from the treatment compared with the control	[114]
Paclitaxel oleate (PTX) and didodecyl methotrexate (MTX)	Lipid core nanoparticles (LDE)	Lipid mixture (Cholesterol oleate, phosphatidylcholine, triglycerides and cholesterol)	LDE-PTX and LDE-MTX = 45–60 nm	LC = 60 mg of PTX or MTX were added in 322 mg of lipids	IV injection	4 mg/kg of PTX and MTX, injected once per week for 4 weeks	Male NZ white rabbits. 1% cholesterol diet- 8wks	LDE is taken up by the cells through the LDL receptor mediated endocytic pathway	The combination therapy of LDE-PTX + LDE-MTX shows decreased lesion area of the total artery (19%) compared to the control (63%)	[115]
Docetaxel (DTX) (derivatized to enhance lipophilicity)	Lipid core nanoparticles (LDE)	Lipid mixture (Phosphatidylcholine, esterified cholesterol, non-esterified cholesterol and triglycerides)	60 nm	1:10 ratio of DTX to LDE	IV injection	1 mg/kg once a week for 4 weeks	Male NZ white rabbits. 1% cholesterol diet- 8wks	LDE is taken up by the cells through the LDL receptor mediated endocytic pathway	LDE-DTX showed 80% less atherosclerotic area vs. LDE control The microscopic lesions and VSMCs in intima were 85% lower in LDE-DTX vs. LDE control.	[116]
Rosiglitazone (Rosi)	Lipid latex (LiLa) nanoparticles	PtdSer, 9-CCN, and phosphatidylethanolamine-PEG2000	65 ± 10 nm	LC (mg/1 mg latex); Rosi = 0.59 ± 0.15; TAM = 0.48 ± 0.39; PAX = 0.14 ± 0.07	No in vivo study	–	In vitro model using RAW 264.7 macrophages	Phosphatidylserine (PtdSer) and oxidised cholesterol ester derivative cholesterol-9-carboxynonanoate (9-CCN) which promote phagocytosis by macrophages	Rosi-LiLa model displayed a higher loading capacity Preferential uptake of LiLa NPs in RAW cells Free Rosi and Rosi-LiLa showed significant decrease in the concentration of proinflammatory cytokines.	[117]
Paclitaxel (PTX)	Mesoporous silica nanomotor	Fe3O4 nanoparticles, amine modified mesoporous silica nanoparticles	450 nm; −11.85 mV	20 mg of PTX in 20 mg of amine-modified mesoporous silica	Direct delivery by drug-coated balloons	20 mg of PTX	NZ white rabbits	Anti VCAM-1 polyclonal antibody binding to VCAM-1	The plaque area of the nanomotor treatment group was smaller compared to the PTX only control group No damage was observed in the blood vessels due to photothermal treatment	[118]