Table 4.

Nanoparticle strategies for the delivery of other small molecule drugs 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
CCR2 antagonist (Teijin compound 1)	Target sensitive liposome (TSL)	DOPE, DOPA and Mal-PEG-DSPE	128 ± 19 nm	N/A	–	N/A	ApoE−/− mice aortas used for in situ study	VCAM-1 targeting peptde (VHPKQHRGGSKGC) binding to VCAM-1	In vitro tests of the target sensitive liposome coupled with a VCAM-1 peptide (Vp-TSL) binds to the cells expressing VCAM-1 and releases Teijin The targeted liposomes showed a 78% release of Teijin after 6 h compared to the ∼30% in the non-targeted liposomes The inhibition of monocyte/macrophage infiltration into the aorta of ApoE−/− mice were shown in situ.	[122]
synthetic LXR agonist GW3965 (GW)	Polymeric Nanoparticle	PLA, DSPE, mPEG, DLPC	83.9 ± 2.6 nm; 1.8 ± 0.8 mV	LE: 45%	IV injection	8 mg/kg, twice a week for 5 weeks	LDLR−/− mice	Collagen IV binding peptide (KLWVLPKGGGC) targeting Collagen IV	Decrease in plaque macrophages by ∼30% compared with free drug Hepatic triglyceride and cholesterol were lower on Col (IV) GW-NPs compared to PBS whereas free GW showed increased levels	[123]
LXR agonist GW3965	Polymeric Nanoparticle	PLGA-b-PEG	156.6 ± 10.3 nm	LE = 58.8 ± 1.3% LC = 9.8 ± 0.2%	RO injections	10 mg/kg, 3 times a week for 2 weeks	LDLR−/− mice	Phosphatidylserine (PS) lipid which promote phagocytosis by macrophages	Reduction in the CD68-positive macrophage content in lesions by 50% No increase in triglycerides or total cholesterol in the plasma and liver Decreased the inflammation and increased the LXR gene expression compared to free GW3965.	[124]
SRT1720	Mesoporous silica Nanoparticle	Silica	61.4 ± 7.9 nm; 8.6 ± 0.3 mV	LC = 47 ± 4%; LE = 42 ± 2%	Intraperitoneal injection	170 mg/kg per day, every other day for 4 weeks	ApoE−/− mice RAW264.7 mouse cells were used for in vitro	AntiCD36 antibody targeting the CD36 receptor expressed on the surface of macrophages	Decrease in the blood total cholesterol was observed in vitro with inhibition of macrophage foaming A significant improvement in the serum total cholesterol and aortic plaque Enhanced therapeutic efficacy of NP-SRT1720 compared to the free drug ∼32% decrease in plaque area of the whole aorta in the treatment group compared to the model	[125]
Rapamycin	Polymeric Nanoparticle	β-cyclodextrin (β-CD)	RAP/Ac-bCD NP (186.5 ± 1.6 nm, −34.3 ± 1.4 mV) RAP/Ox-bCD NP (253.5 ± 3.9 nm, −22.8 ± 0.5 mV)	LC: RAP/PLGA NP (8.0%); RAP/Ac-bCD NP (12.5%); RAP/Ox-bCD NP (7.0%)	Intraperitoneal injection	3 mg/kg every 3 days for 2 months	ApoE−/− mice	N/A	Both types of stimuli responsive therapies delayed the progression of atherosclerosis Enhanced the stability of atherosclerotic lesions Plaque area decreased from 30.2% (model group) to 5.1% (RAP/Ac-bCD) and 4.5% (RAP/Ox-bCD)	[126]
Pioglitazone	Polymeric Nanoparticle	PLGA	247 nm diameter	N/A	IV injection	7 mg/kg per week for 4 weeks	ApoE−/− mice	N/A	NP mediated delivery of pioglitazone in mouse model inhibited atherosclerotic plaque destabilisation and rupture The polarity of the macrophages was regulated to be less inflammatory No significant difference in the plaque area between treatment and control groups	[127]
1,25-dihydroxyvitamin D3 (aVD) and ApoB-100-derived antigenic peptide P210	Polymeric Nanoparticle	poly (ethylene glycol)-bl-poly (propylene sulfide) (PEG-b-PPS)	143.6 nm; −5.32 ± 1.24 mV	LC = 12.5 μg P210/100 ng aVD/1.5 mg polymer	IV injection	1 μg/ml of aVD in 100 μL, injected every week for 8 weeks	ApoE −/− mice	P-D2 peptide (GGVTLTYQFAAGPRDK) binding to the CD11c present on the surface of dendritic cells	Decreased atherosclerotic lesions and presence of macrophages in the P210/P-D2-PEG5-PS-aVD group compared to the control, free aVD and aVD loaded PS.	[128]
SHP1i (a small-molecule inhibitor of CD47's downstream effector molecule)	Carbon nanotube	Single walled carbon nanotubes	5–6 nm diameter, >60 nm length −7.19 ± 2.53 mV	N/A	IV injection	N/A	ApoE−/− mice	N/A	Promoted efferocytosis resulting in the reduced lesion area and necrotic core	[129]
Superoxide dismutase mimetic agent (Tempol) and hydrogen peroxide-eliminating compound	Polymeric Nanoparticle	β-cyclodextrin (β-CD)	128 ± 1 nm	N/A	IV injection	100 mg/kg of NP (17.2 mg/kg of Tempol) for 9 weeks	ApoE−/− mice	Passive targeting by EPR	Decreased necrotic core with thicker fibrous cap Plaque stabilised with fewer cholesterol crystals Decreased levels of macrophages and matrix metalloproteinase-9 levels Decreased average plaque area from 24.9% (control) to 6.3% (treatment group)	[130]