Nanomedicine-based formulations containing ω-3 polyunsaturated fatty acids: potential application in cardiovascular and neoplastic diseases

Figures & data

Table 1 Application of ω-3 PUFA nanoformulations in cardiovascular disease settings

Nanoparticle (NP) type	Chemical form of ω-3 PUFA used	NP size (nm)	EE (%)	Cargo molecule	Zeta potential (mV)	Function of the NP	Experimental model	Mechanisms involved in the NP effects	Reference
ALA-rich* flaxseed oil-based oil-in-water nanoemulsion	ALA-rich (56% by weight) flaxseed oil	138–144	92–98	CER and/or 17-βE	32.30±1.81 (CER) 33.80±2.45 (17-βE)	To improve 17-βE and/or CER internalization in vascular cells	Human EC and VSMC in vitro	Increased CER and 17-βE uptake by cultured cells; increased EC and decreased VSMC proliferation (p38 MAPK inhibition)	^Citation17
ALA-rich* flaxseed oil-based oil-in-water nanoemulsion	ALA-rich (56% by weight) flaxseed oil	176	94.6	CREKA and 17-βE	33.80±2.45 (17-βE); NR (CREKA)	To improve 17-βE internalization in vascular cells	Human EC in vitro; IV administration to apoE−/− high-fat diet mice	Increased NO production by EC in vitro; decreased atherosclerotic plaque size in mice; improved plasma lipid profile in mice; reduced ICAM-1, VCAM-1, IL-6, TNF in mice atherosclerotic plaque	^Citation18

Note:

* 56% by weight.

Abbreviations: ALA, α-linolenic acid; CER, ceramide; CREKA, cysteine–arginine–glutamic acid–lysine–alanine peptide; 17-βE, 17β-estradiol; EC, endothelial cells; EE, encapsulation efficiency; IV, intravenous; MAPK, mitogen-activated protein kinase; NO, nitric oxide; NR, not reported; PUFA, polyunsaturated fatty acid; VSMC, vascular smooth muscle cells; TNF, tumor necrosis factor.

Figure 1 Potential use of ALA-containing nanoemulsions against the development of restenosis and atheroma.

Note: The biological activity of nanoemulsions were evaluated in vitro or in vivo.

Abbreviations: ALA, α-linolenic acid; 17-βE, 17β-estradiol; CER, C6-ceramide; CREKA, cysteine–arginine–glutamic acid–lysine–alanine.

Table 2 Application of ω-3 PUFA nanoformulations in liver cancer

Nanoparticle (NP) type	Chemical form of ω-3 PUFA used	NP size (nm)	EE (%)	Cargo molecule	Zeta potential (−mV)	Function of the NP	Experimental model	Mechanisms involved in the NP effects	Reference
LDL-based nanoparticles	Unesterified DHA incorporated in LDL	18.3	13	DHA	22	To enhance physical, oxidative stability, and delivery of DHA to target cells	Normal TIB-73 and neoplastic TIB-75 murine hepatocytes in vitro	Enhanced oxidative and physical stability of LDL-based nanoparticles over free DHA; selective cytotoxicity toward cancer cells	^Citation12
LDL-based nanoparticles	Unesterified DHA incorporated in LDL	18.3	13	DHA	Not reported	To enhance physical, oxidative stability, and delivery of DHA to target cells	Rat and human HCC cell lines in vitro; mice transplanted with human HCC cells	Enhanced tumor cell death through ferroptosis; reduced tumor volumes in transplanted mice	^Citation27
LDL-based nanoparticles	Unesterified DHA incorporated in LDL	18.3	13	DHA	24±2.6	To enhance physical, oxidative stability, and delivery of DHA to target cells	Normal TIB-73 and neoplastic TIB-75 murine hepatocytes in vitro	Selective cytotoxicity toward cancer cells through an impairment of lysosomal, mitochondrial, and nuclear function	^Citation28
LDL-based nanoparticles	Unesterified DHA incorporated in LDL	18.3	13	DHA	25	To enhance physical, oxidative stability, and delivery of DHA to target cells	H4IIE rat hepatoma cells IV injected in rats	Reduced tumor volumes; tumor-specific necrosis induced by selective redox balance alteration within cancer cells	^Citation29
Tuftsin-tagged liposomes	ALA esterified to 2,6-di-isopropylphenol (propofol)	100–130	74	2,6-propofol ALA conjugate	43.23±1.4	To enhance the delivery and anticancer activity of ALA in target cells	Mice subject to DEN-induced hepatocarcinoma	Increased mice survival; reduced expression of COX-2 and Bcl-2; increased expression of Bax in hepatocarcinomas	^Citation41

Abbreviations: ALA, α-linolenic acid; DEN, diethylnitrosamine; DHA, docosahexaenoic acid; EE, encapsulation efficiency; HCC, hepatocellular carcinoma; IV, intravenous; LDL, low-density lipoproteins; PUFA, polyunsaturated fatty acid.

Figure 2 Omega-3 PUFA-containing nanomaterials developed and evaluated in vitro or/and in vivo for their potential use against liver (A), breast (B) and lung (C) cancer.

Abbreviations: DHA, docosahexaenoic acid; LDL, low-density lipoprotein; LNA, linolenic acid; PEG, polyethylene glycol; PL, phospholipids; PεCL, poly-ε-caprolactone; PUFA, polyunsaturated fatty acid; SLN, solid lipid nanoparticle.

Table 3 Application of ω-3 PUFA nanoformulations in breast cancer

Nanoparticle (NP) type	Chemical form of ω-3 PUFA used	NP size (nm)	EE (%)	Cargo molecule	Zeta potential (−mV)	Function of the NPs	Experimental model	Mechanisms involved in the NP effects	Reference
Polymeric PεCL nanocapsules	DHA-free fatty acid	183	NR	DHA	29.7±0.7	To protect DHA from oxidation; to provide a delivery system to be used orally (through a higher resistance to adverse environmental conditions of GI tract)	Human breast epithelial MCF-10A and tumor MDA-MB-231 cancer cells in vitro	Inhibition of cell proliferation (MTT assay) (only in the presence of H2O2 within the nanoparticle)	^Citation50
PEGylated liposomes	DHA-free fatty acid	99	81.4	DHA	15.7±2.5	To enhance cell permeability and retention and facilitate local delivery of DHA	Murine 4T1 breast cancer cells in vitro; murine RAW264.7 and human THP-1 monocytes in vitro	Inhibition of cancer cell proliferation (BrdU assay); decreased inflammation (reduced MCP-1 and TNF-α production by monocytes)*	^Citation58
Phytanyl lipid-based liposomes	DHA-sodium salt	130–160 (depending on pH values)	60–80	DHA	1.6	To enhance DHA chemical and oxidative stability	Human MDA-MB-231 and MCF-7 breast cancer cells in vitro	Reduction of cell viability (MTT assay); increased apoptosis; reduced p-Akt expression#	^Citation60

Notes:

* Compared to unloaded nanoparticles or free ω-3 PUFA.

# Compared to free DHA.

Abbreviations: DHA, docosahexaenoic acid; EE, encapsulation efficiency; GI, gastrointestinal; NR, not reported; PEGylated, polyethyleneglycolylated; PεCL, poly-ε-caprolactone; PUFA, polyunsaturated fatty acid; TNF, tumor necrosis factor.

Table 4 Application of ω-3 PUFA nanoformulations in lung and prostate cancer

Nanoparticle (NP) type	Chemical form of ω-3 PUFA used	NP size (nm)	EE (%)	Cargo molecule	Zeta potential (−mV)	Function of the NP	Experimental model	Mechanisms involved in the NP effects	Reference
SLN	DHA-free fatty acid	94 (0.4% DHA)	99 (0.4% DHA)	DOX ± DHA	34±0.2 (0.4% DHA)	To reduce SLN size; to induce negative charges in SLN; to enhance DOX EE, release in medium and solubility in lipids	Human A549 lung adenoCa cells in vitro	Enhanced DOX cytotoxicity§ (TB exclusion assay)	^Citation64
DHA-BSA polymeric nanoparticles	DHA-free fatty acid	146.9±22.9	98.6±9.3	DTX	31.5±1.5	To specifically target cancer cells	Murine LLC cells and human A549 adenoCa in vitro; murine LCC cells transplanted in C57BL/6 mice	¥In vitro: enhanced cancer cell targeting; enhanced cell uptake efficiency; enhanced DTX antiproliferative effect (MTT assay); decreased cancer cell migration. @In vivo: decreased lung cancer metastases to bone; increased mice survival	^Citation65
Oil-in-water nanoemulsion	DHA-SBT-1214 conjugate	228±7	97	DHA-SBT-1214	24.9±4.3	To enhance permeability and retention of SBT-1214 in cancer cells	Human CSC-enriched PPT2 prostate cancer cells in vitro and transplanted in NOD/SCID mice	Enhanced drug cytotoxicity in vitro*; enhanced tumor growth suppression in vivo*	^Citation87
Oil-in-water nanoemulsion	DHA-SBT-1214 conjugate	213.2	97	DHA-SBT-1214	28.9±4.3	To improve the targeted delivery of SBT-1214 to cancer cells	Human CSC-enriched PPT2 prostate cancer cells transplanted in NOD/SCID mice	Slower in vitro drug release; improved pharmacokinetic properties in plasma and tissues; enhanced stability#	^Citation88

Notes:

§ Compared to free DHA + DOX and to empty SLN.

¥ Compared to free DTX or to DTX-BSA nanoparticles.

@ Compared to DTX-BSA nanoparticles.

* Compared to both Abraxane^® and placebo nanoemulsion formulation.

# Compared to aqueous solution.

Abbreviations: EE, encapsulation efficiency; LLC, Lewis lung carcinoma; NOD, nonobese diabetic; SCID, severe combined immunodeficiency; SLN, solid lipid nanoparticles; adenoCa, adenocarcinoma; CSC, cancer stem cells; DHA, docosahexaenoic acid; DOX, doxorubicin; DTX, docetaxel; PUFA, polyunsaturated fatty acid.

Figure 3 Omega-3 PUFA-containing nanomaterials developed and evaluated in vitro or/and in vivo for their potential use against prostate (A), melanoma (B), and colorectal cancer (C).

Abbreviations: PUFA, polyunsaturated fatty acid; DHA, docosahexaenoic acid; SLN, solid lipid nanoparticle; ALA, α-linolenic acid.

Table 5 Application of ω-3 PUFA nanoformulations in melanoma and colon cancer

Nanoparticle (NP) type	Chemical form of ω-3 PUFA used	NP size (nm)	EE (%)	Cargo molecule	Zeta potential (−mV)	Function of the NP	Experimental model	Mechanisms involved in the NP effects	Reference
α-Tocopheryl linoleate-based SLN	ALA-free fatty acid	181	77	ALA	ND	To improve the delivery and stability of ALA	Human C32 melanoma cells in vitro	Enhanced antioxidant efficiency*; enhanced cytotoxicity#	^Citation91
Resveratrol-based SLN	ALA- or DHA free fatty acids	842 (DHA-containing SLN); 1000 (ALA-containing SLN)	77 (ALA); 100 (DHA)	DHA or ALA	ND	To protect ω-3 PUFA from degradation and to increase their incorporation in cancer cells	Human HT29 and HCT116 colon cancer cells in vitro	Increased ω-3 PUFA incorporation in tumor cells; increased cancer cell growth inhibition; reduced cancer cell proliferation§	^Citation92

Notes:

* Compared to the empty SLN.

# Compared to free ALA.

§ Compared to free DHA and ALA.

Abbreviations: ALA, α-linolenic acid; DHA, docosahexaenoic acid; EE, encapsulation efficiency; ND, not determined; SLN, solid lipid nanoparticles; PUFA, polyunsaturated fatty acid.

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