Innovative Therapies and Nanomedicine Applications for the Treatment of Alzheimer’s Disease: A State-of-the-Art (2017–2020)

Figures & data

Table 1 Characteristics of the Most Promising Brain-Targeting Functionalized NPs Listed in the Text

Specific Target	NPs		Characteristics				REF
			Mean Size (nm)	Polydispersity Index	Zeta Potential (mV)	Encapsulation Efficiency (%)
Aβ plaques, tau fibrils	mf-LIPs		155 ±30	0.213±0.055	−3.31±1.51	NA	125
	PEG-BTH-nanoliposomes		102–109	170±0.005	−3.13 ± 0.235 −2.27 ± 0.165)	NA	126
	NPs functionalized Aβ1-42 monoclonal antibody		125	0.1–0.2	−20 to −30	NA	46
	PEGylated nanosweepers composed of cationic CS		200	NA	NA	NA	47
	TA–AuNP		21.6 ± 2.4	0.235	−30 and −40	NA	48
	Sulfur NPs	Met@TS	120.21±4.36	NA	−34.2±0.45	NA	49
		RVG@Met@TS	123.12±4.27	NA	−35.2±0.36	NA
		Met@VS	109.15±3.56	NA	−33.7±0.42	NA
		RVG@Met@VS	110.25±3.29	NA	−36.8±0.29	NA
		Met@SS	52.33±1.27	NA	−36.2±0.39	NA
		RVG@Met@SS	56.57±2.23	NA	−37.6±0.21	NA
	OPCDs		7.3	NA	17,4	NA	50
	IDA-NPs		88.0 ± 5.9	NA	−41.3 ± 7.7	NA	51
	D-Pen@Se NPs		113.5	0.31	− 8.36	NA	52
	PEG/CS-PZn NPs		NA	NA	15	12.5 ± 1.2	53
	CMCDs		1–5	NA	NA	NA	54
	MoO3−x nanodots		31 ±0.7	NA	−13.4 ± 1.6	58.5 Mo^6+; 41.5 Mo^5+	54
	β-NaYF4:Yb/Er		38.3 ± 3.7	NA	NA		55
	KLVFF-PLGA NPs		216 ± 34	0,25 ± 0.03	−34 ± 3	NA	56
	D/L-FexCuySe NPs		50	NA	NA	NA	57
	DBP-PLGA		226.6 ± 44.4	0.039 ± 0.013	−0.144	89.3 ± 3.3	59
	Nicotinamide-loaded SLNs	S80-SLN (Polysorbate80)	112 ± 1.6	NA	NA	1	60
		PS-SLN (Phosphatidylserine)	124 ± 0.8	NA	−46.1 ± 0.6	5
		PA-SLN (Phosphatidic acid)	137 ± 1.05	NA	−50.6 ± 0.8	10
	PC-CdS NPs		50–60	NA	NA	NA	61
	HMPWCs		10–30	NA	−30	NA	62
	CS@Se		89.1 ± 4.5	0.27 ± 0.05	−41.7 ± 3.5	NA	63, 64
Reducing intracellular calcium	Amlodipine functionalized nanodiamond particles		31.1 ± 8.2	NA	NA	NA	69
	Lomerizine modified nanospheres (LNP+PEI)		210	NA	NA	7.1 ± 1.3	71
	Felodipine loaded NPs		651 ±2.10	0.780 ± 0.074	14.1 ± 0.67	68.78 ± 0.680	72, 73
	Nimodipine encapsulated in Chitosan NPs		5.2 ± 1.1	NA	NA	NA	74
PPARs agonists	Polymeric PLGA-PEG NPs carrying PGZ		155.0 ± 1.8	0.1	−13.0 ± 0.5	92.5	76
Neuronal regeneration	Iron oxide NPs NGF-MNPs		45 ± 17	NA	NA	NA	78
	SPIO–AuNPs		20.8 ± 2.7	NA	−25.1	NA	79, 80
	6MP-AuNPs-RDP		24.6	NA	−25.8	NA	81

Abbreviations: mf-LIPs, multifunctional liposomes with TREG-mAPOE and Mab; TA–AuNP, tannic acid–stabilized gold nanoparticle; OPCDs, polymerized o-phenylenediamine-derived carbon dots; IDA-NPs, iminodiacetic acid-conjugated NPs; D-Pen@Se NPs, D-penicillamine-capped selenium NPs; PEG/CS-PZn NPs, PEG-modified-CS-NPs loaded with a Zn(II); CMCDs, cow milk-derived carbon dots; β-NaYF4:Yb/Er, upconverted NPs co-doped it with rare earth elements, ytterbium and erbium; KLVFF-PLGA NPs, PLGA NPs functionalized with KLVFF; D/L-FexCuySe NPs, Chiral Iron Copper Selenide NPs; DBP-PLGA, PLGA NPs functionalized with a vitamin D-binding protein; PC-CdS NPs, protein-capped metal NPs; HMPWCs, manganese Prussian white NPs; CS@Se, chondroitin sulphate nano-selenium; 6MP-AuNPs-RDP, AuNPs loaded 6-mercaptopurine functionalized peptide RDP; NA, not available.

Figure 1 Summary of the strategies to overcome or bypass the BBB.

Notes: Adapted from Stanfield CL, Germann WJ. Fisiologia Terza Edizione. [Physiology Third Edition] with permission from EdiSES srl¹⁶ and adapted with permission from Focused Ultrasound Foundation.¹⁷

Abbreviations: CMT, carrier-mediated transport; RMT, receptor-mediated transcytosis; ICV, intracerebroventricular; IN route, Intranasal route; CSF, Cerebrospinal fluid.

Table 2 Mean Characteristics and Principal in vitro and in vivo Results of Nutraceuticals Loaded Nanoformulations

Nutraceutical	NP	Characteristics				RESULTS		REF
		Mean Size (nm)	Polydispersity Index	Zeta Potential (mV)	Encapsulation Efficiency (%)	In Vitro	In Vivo
Resveratrol	SLNs	142 ± 10	0.12 ± 0.04	−0.08 ± 0.05	75–100%	In BBB models (human endothelial cells/pericytes and hCMEC/D3 cells): improved BBB passage		74
	Nano capsules	249 ± 5	0.12 ± 0.05	−14 ± 1.8	99.89 ± 1.3		In Aβ-injected AD rat model: impaired learning and memory abilities, increased astrocyte and microglia recruitment
Quercetin	PLGA	100–150	NA	NA	NA	In SH-SY5Y cells: reduced Zn^2+-Aβ42-induced cytotoxicity	In APP/PS1 mouse model: ameliorated spatial learning and memory impairments without signs of adverse effects	78
	SLNs	234±18	0.06±0.01	−32±8	77±11	In hCMEC/D3 cells (BBB model): high BBB permeability		75
	SNPs-MB	NA	NA	NA	NA	In a bEnd.3 cells/SH-SY5Y BBB model: improved NPs entry In SH-SHY5Y cells: reduced ER stress levels and ER stress-mediated hallmarks (inflammatory response, calcium homeostasis imbalance, and oxidative stress)	In APP/PS1 mouse model: reduced Aβ deposition and neuronal loss, improved learning and memory behavior	34
Anthocyanins	PLGA	165	0.4	−12	60	In SH-SY5Y cells: increased cell viability against Aβ42, abrogated ROS generation, attenuated AD and neuroapoptotic markers		77
	AuNPs	135 ± 5	0.5	−11.5 ± 2	34	In BV2 cells: prevented tau hyperphosphorylation, reduced protein expression levels of neuroinflammatory and neuroapoptotic markers	In Aβ-injected AD mouse model: prevented tau hyperphosphorylation, reduced microglia and astrocytes activation, reduced neuroinflammatory and neuroapoptotic markers, attenuated neurodegeneration In Aβ-injected AD mouse model: prevented tau hyperphosphorylation, reduced protein expression levels of apoptosis and neurodegeneration markers, mitigated synaptic dysfunctions and ameliorated memory impairments	81 79
Rutin	Lipid polymer hybrid NPs	232.4 ± 4.01	0.339 ± 0.010	−1.76 ± 0.33	68.06 ± 1.50	In erythrocytes separated from rat blood: hemolysis test confirmed biocompatibility	In white male albino rats: biodistribution study confirmed brain accumulation	78
HST	Nanocrystals	NA	NA	NA	NA		In unilateral icv-STZ rat AD model: improved memory functions, reduced levels of hippocampal oxidative stress	82
Curcumin	Nanogels	201 ± 19	NA	− 25.2 ± 2.0	NA	In SH-SY5Y cells: protected cells from Aβ-induced cytotoxicity		74
	Polymeric NPs	197 ± 2.3	0.18	−22.44 ± 2.3	77.99 ± 0.91	In SH-SY5Y cells: protected cells from Aβ-induced cytotoxicity In SK-N-SH cells: protected cells from oxidative stress damages
	Liposomes	168.9±1.3	0.164	20.3±1.4	NA		In APP/PS1 mouse model: acted on Aβ aggregates
Berberine	Multi-walled carbon nanotubes	125–295	0,3–0,25	NA	NA	In SH-SY5Y cells: efficient cellular uptake of the NPs	In Aβ-injected AD rat model: recovered memory performance, reduced Aβ aggregates and oxidative stress damages	93
α-bisabolol	SLNs	139.5	0.244	−31.7	98.44	In Neuro-2A cells: reduced Aβ-induced free radicals levels and oxidative stress damages, showed neuroprotection from Aβ-induced apoptosis		94
Apocynin	Poly anhydride NPs	385±1,17	0.029	−12.5 ± 4.7	42.7 ± 1.8	In N27 cells: no signs of cytotoxicity, NPs internalization In primary cortical neurons: no signs of cytotoxicity, NPs internalization, protection against oxidative stress damages In LUHMES cells: protection against oxidative stress damages		95
Ginsenoside Rg3	PLGA	115	0.081	NA	65–70	In C6 cells: cellular uptake In THP-1 cells: reduced Aβ-induced amyloid plaques formation, oxidative stress damages and pro-inflammatory cytokines levels, reduced expression of gene encoding the β-amyloid A4 precursor In BMVECs/C6 cells BBB model: BBB crossing		96
Phytol	PLGA	177.4 ± 5.9	0.2 ± 0.06	−32.8 ± 2.2	92.14 ± 0.29	In Neuro-2A cells: protected cells from Aβ-induced cytotoxicity		97
EGCG	PLGA	124.8 ± 5.2	0.054 ± 0.013	−15.1 ± 1.7	97.1 ± 2.4	In primary brain microvascular endothelial cells (BBB model): alterations of the BBB integrity through tight junctions disruption	In APP/PS1 mouse model: increased synapses, reduced amyloid plaques and neuroinflammation, ameliorated spatial learning and memory abilities	98
RIN	PLGA	145.2	0133	NA	60	In erythrocytes separated from rabbit blood: hemolysis test confirmed biocompatibility In bEnd.3 cells (BBB model): high intracellular uptake and passage In PC12 cells: reduced apoptosis due to Aβ-induced cytotoxicity	In C57BL/6 mice: biodistribution study confirmed brain accumulation	99

Abbreviations: SLNs, solid lipid nanoparticles; PLGA, poly(lactide-co-glycolide); AuPdNPs, gold/palladium nanoparticles; SNPs-MB, sulfur nanoparticles in microbubbles; HST, hesperetin; Icv, intracerebroventricular; STZ, streptozotocin; EGCG, epigallocatechin-3-gallate; RIN, rhynchophylline .

Stanfield CL, Germann WJ. Il Sistema Nervoso; il Sistema nervoso Centrale [The Nervous System; the Central Nervous System]. In: Molinari CG, Marini HR, editors. Fisiologia Terza Edizione. [Physiology Third Edition]. Naples, Italy: EdiSES Srl; 2009:216–251. Italian.

 Google Scholar

Freeman T. Focused ultrasound opens the blood-brain barrier. Physics World Available from: https://physicsworld.com/a/focused-ultrasound-opens-the-blood-brain-barrier-2/. Accessed 8 4, 2020.

 Google Scholar