Nanoformulations of natural products for management of metabolic syndrome

Figures & data

Table 1 Phytochemical-based nanoformulations for management of metabolic syndrome (MetS)

Phytochemical	Nanoformulation	Disorder	Cellular/animal model	Dose	Size	Outcome	Reference
Curcumin	PBLG-PEG-PBLG	Diabetic cardiomyopathy	Diabetic rats and H9C2 cells	20 mg/kg	30 nm	↑H2S, ↑CaSR, ↑CSE, ↑CaM	^Citation77
	CNPs @GMs/hydrogel	Diabetic wound	STZ-induced diabetic rats		4 to 8 µm	↑GSH ↓ROS	^Citation84
	SNEDDS	Diabetic neuropathy	STZ-induced diabetic rats	66.7 mg/kg	170 nm	↓TNF-α ↓IL-6	^Citation78
	PLGA-PVA polymers	Diabetic cataract	STZ-induced diabetic cataract model	2 mg/day	282±5.72 nm	↓VEGF ↑cellular uptake, bioavailability	^Citation79
	Pluronic nanomicelles	STZ-induced diabetes	STZ-induced diabetic rats	100 mg/kg	333±6 nm	↑Pdx-1 and NKx6.1	^Citation80
	PLGA-based NPs with Q10	Diabetes complications	STZ-induced diabetic rats	100 mg/kg	237±6 nm	↓CRP, IL-6, total cholesterol, ↓plasma triglycerides ↑HDL	^Citation81
	Curcumin nanoemulsion	Hypertension and hypercholesterolemia	In vitro study		42.93±29.85 nm	Inhibition of HMGR along with ACE	^Citation65
	PEGMA-DMAEMA-MAO	Diabetic peripheral neuropathy	STZ-induced diabetic rats	4 mg/kg		↓IL-1β ↓p-AKt P2Y12 receptor on SGCs in the DRG	^Citation83
Capsicum oleoresin	Nanoemulsion	Obesity	High-fat (HF)-diet-induced obesity in rats	0.1 mL/80 g body weight	20–50 nm	↓Adipogenic gene expression ↑PPAR-α, UCP2 and CPT-1α	^Citation90
Alginate double-layer nanoemulsion	Obesity	HF-diet-induced obesity in rats and 3T3-L1 cell line	1,000 ng/mL		↓mRNA levels of PPAR-γ ↓fatty acid binding protein adipocyte protein-2 hormone-sensitive lipase ↑carnitine ↑palmitoyl transferase-1α ↑HSL and CPT-1α genes ↓PPAR-γ and aP2	^Citation91
Berberine	Solid lipid nanoparticles (SLNs)	Diabetes	db/db diabetic mice	100 mg/kg	76.8 nm	↓Body weight, fasting blood glucose levels, HOMA-IR ↑impaired glucose tolerance	^Citation98
	O-hexadecyl-dextran	High glucose stress induced apoptosis in hepatocytes	Primary hepatocytes cells derived from the liver of Sprague-Dawley rats	0.125 mg to 2.0 mg	238±18 nm	↓ROS ↓Caspase activation ↓Oxidative stress	^Citation99
	PLGA-PEG-PLGA block copolymers	High LDL cholesterol	Hep-G2 cells		42–63 nm	Modulation of PCSK-9 mRNA	^Citation100
Naringenin	Alginate-coated chitosan core-shell	Diabetes	STZ-diabetic rats		150–300 nm	No toxicity, better therapeutic effect	^Citation128
Quercetin	(QUE/P) NP	Diabetic nephropathy	Diabetic rats	10 mg/kg	32 nm	Downregulation of ICAM-1 expression	^Citation113
	pH sensitive chitosan-alginate core-shell	Diabetes	Human colonic epithelial cell line HT29 and STZ-induced diabetic rats	100 mg/kg	91.58 nm	↓Serum AST, ALT and ALP levels	^Citation114
	PLGA NPs	Diabetes	STZ-induced diabetic rats	150 mg/kg	179.9±11.2 nm	↑CAT and SOD levels ↓Drug doses	^Citation116
	Nanoemulsion	Oxaliplatin-induced neuro- and hepatotoxicity	BALB/c mice	20 mg/kg		↓Inflammation, pain, and apoptosis exploited by oxaliplatin and prevented oxaliplatin-induced neuro- and hepatotoxicity	^Citation115
	Quercetin nanorods	Diabetes	Alloxan-induced diabetic rats	20 mg/kg body weight	15.4 nm	↓FBG level in blood ↓G6Pase and FBPase ↓SOD, CAT, GSH, and –SH ↓AST, ALP, and ALT	^Citation117
Emodin	PEGMA-DMAEMA-MAMMAM nanomacromolecule	Diabetic neuropathic pain	T2DM induced by HFdiet with low dose of STZ injection in rats	1 mg/mL per rat		↓Upregulation of TNF-α protein, P2X3 receptor, and the phosphorylation of ERK1/2 in the DRG of T2DM	^Citation120
Nano emodin transferosome	Antiobesity	HF-diet-induced obesity in rats		292.2 nm	Upregulation of ATGL protein expression, downregulation of G0S2 protein expression, body weight, and adipocyte size	^Citation121
Gymnemic acid	Nanosuspension	Diabetes	Diabetes-induced rats			↓Blood glucose levels	^Citation124
Baicalin	Nanostructured lipid carriers	Diabetes	STZ-induced diabetic rats		92±3.1 nm	↓FBS, HbA1c, and TG levels	^Citation128
Scutellarin	Amphiphilic chitosan derivatives (Chit-DC-VB12)	Diabetic retinopathy	Caco-2 cells and STZ-induced diabetic rats		150–250 nm	Downregulation of expression of VEGFR2, VEGF, and vWF	^Citation132
Resveratrol	Nanoliposomes	Diabetes mellitus	STZ-induced diabetic cells	30 µg/mL of resveratrol	215 nm	↑ROS-inactivating enzymes including GSH-Px and SOD	^Citation143
Nanocapsule	Blood pressure regulation	HF-diet- induced diabetic mice		207 nm	Regulation of systolic and diastolic blood pressure	^Citation144
Silybin	PLGA polymers	Systemic hyperglycemia	STZ-induced diabetic rats			↑Antioxidant characteristics, regenerative impacts on beta cells' membrane permeability	^Citation149
Myricitrin	SLNs	Diabetes	Hyperglycemic myotube cells and STZ-nicotinamide- induced T2DM mouse		76.1 nm	Improvement of SOD level, ↑muscle and myotube glycogen content, Glut4 gene expression in skeletal muscle and C2C12 cells, Bcl-2 gene expression, Bax to Bcl-2 ratio of myotubes	^Citation153
Stevioside	Pluronic-F-68 copolymer-based PLA nanoparticles	Diabetes	In vitro release study	10 mg NPs	110–130 nm	↑Intestinal absorption, bioavailability ↑Biocompatibility controlled release	^Citation156
α-eleostearic	Bitter Gourd Seed Oil Nanoemulsion	Diabetes mellitus	Alloxan-induced diabetic rats	0.5% and 1%	<100 nm	↑PPAR-γ ↑GPx, SOD, and CAT	^Citation158

Abbreviations: PBLG-PEG-PBLG, poly (gamma-benzyl l-glutamate)-poly (ethylene glycol)-poly (gammabenzyl l-glutamate); H₂S, hydrogen sulfide; CNPs @GMs, curcumin nanoparticles@ gelatin microspheres; STZ, streptozotocin; SNEDDS, self-emulsifying drug delivery system; PLGA-PVA, Poly (lactic-co-glycolic acid)-Polyvinyl alcohol; HDL, high-density lipoprotein; SGCs, satellite glial cells; DRG, dorsal root ganglia; HSL, hormone-sensitive lipase; HOMA-IR, homeostasis assessment of insulin resistance; LDL, low-density lipoprotein; QUE/P, Que/poly (ethylene glycol)-block-(poly(ethylenediamine l-glutamate)-graft-poly(ε-benzyloxycarbonyl-l-lysine)) (PEG-b-(PELG-g-PZLL)); FBG, fasting blood glucose; TG, triglycerides.

Figure 1 A schematic diagram of the mechanism of action of different phytochemicals against metabolic syndrome.

Tong F, Chai R, Jiang H, Dong B. In vitro/vivo drug release and anti-diabetic cardiomyopathy properties of curcumin/PBLG-PEG-PBLG nanoparticles. Int J Nanomedicine. 2018;13:1945. doi:10.2147/IJN.S17762729662310

 PubMed Web of Science ®Google Scholar

Liu J, Chen Z, Wang J, et al. Encapsulation of curcumin nanoparticles with MMP9-responsive and thermos-sensitive hydrogel improves diabetic wound healing. ACS Appl Mater Interfaces. 2018;10(19):16315–16326. doi:10.1021/acsami.8b0386829687718

 PubMed Web of Science ®Google Scholar

Joshi RP, Negi G, Kumar A, et al. SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with diabetic neuropathy: an insight into its mechanism for neuroprotection. Nanomed. 2013;9(6):776–785. doi:10.1016/j.nano.2013.01.001

 PubMed Web of Science ®Google Scholar

Grama CN, Suryanarayana P, Patil MA, et al. Efficacy of biodegradable curcumin nanoparticles in delaying cataract in diabetic rat model. PLoS One. 2013;8(10):e78217. doi:10.1371/journal.pone.007821724155984

 PubMed Web of Science ®Google Scholar

El-Far YM, Zakaria MM, Gabr MM, El Gayar AM, Eissa LA, El-Sherbiny IM. Nanoformulated natural therapeutics for management of streptozotocin-induced diabetes: potential use of curcumin nanoformulation. Nanomedicine. 2017;12(14):1689–1711. doi:10.2217/nnm-2017-010628635562

 PubMed Web of Science ®Google Scholar

Devadasu VR, Wadsworth RM, Kumar MR. Protective effects of nanoparticulate coenzyme Q 10 and curcumin on inflammatory markers and lipid metabolism in streptozotocin-induced diabetic rats: a possible remedy to diabetic complications. Drug Deliv Transl Res. 2011;1(6):448–455. doi:10.1007/s13346-011-0041-325786365

 PubMedGoogle Scholar

Rachmawati H, SORAYA I, Kurniati N, Rahma A. In vitro study on antihypertensive and antihypercholesterolemic effects of a curcumin nanoemulsion. Sci Pharm. 2016;84(1):131–140. doi:10.3797/scipharm.ISP.2015.0527110504

 PubMedGoogle Scholar

Jia T, Rao J, Zou L, et al. Nanoparticle-encapsulated curcumin inhibits diabetic neuropathic pain involving the P2Y12 receptor in the dorsal root ganglia. Front Neurosci. 2018;11:755. doi:10.3389/fnins.2017.0075529422835

 PubMed Web of Science ®Google Scholar

Kim J-Y, Lee M-S, Jung S, et al. Anti-obesity efficacy of nanoemulsion oleoresin capsicum in obese rats fed a high-fat diet. Int J Nanomedicine. 2014;9:301. doi:10.2147/IJN.S5241424403834

 PubMed Web of Science ®Google Scholar

Lee M-S, Jung S, Shin Y, et al. Lipolytic efficacy of alginate double-layer nanoemulsion containing oleoresin capsicum in differentiated 3T3-L1 adipocytes. Food Nutr Res. 2017;61(1):1339553. doi:10.1080/16546628.2017.133955328747860

 PubMedGoogle Scholar

Xue M, Yang M-X, Zhang W, et al. Characterization, pharmacokinetics, and hypoglycemic effect of berberine loaded solid lipid nanoparticles. Int J Nanomedicine. 2013;8:4677. doi:10.2147/IJN.S3746524353417

 PubMed Web of Science ®Google Scholar

Kapoor R, Singh S, Tripathi M, Bhatnagar P, Kakkar P, Gupta KC. O-hexadecyl-dextran entrapped berberine nanoparticles abrogate high glucose stress induced apoptosis in primary rat hepatocytes. PLoS One. 2014;9(2):e89124. doi:10.1371/journal.pone.008912424586539

 PubMed Web of Science ®Google Scholar

Ochin CC, Garelnabi M. Berberine encapsulated PLGA-PEG nanoparticles modulate PCSK-9 in HepG2 cells. Cardiovasc Hematol Disord Drug Targets. 2018;18(1):61–70. doi:10.2174/1871529X1866618020113034029422010

 PubMedGoogle Scholar

Shi F, Wei Z, Zhao Y, Xu X. Nanostructured lipid carriers loaded with baicalin: an efficient carrier for enhanced antidiabetic effects. Pharmacogn Mag. 2016;12(47):198. doi:10.4103/0973-1296.18634727601850

 PubMed Web of Science ®Google Scholar

Tong F, Liu S, Yan B, Li X, Ruan S, Yang S. Quercetin nanoparticle complex attenuated diabetic nephropathy via regulating the expression level of ICAM-1 on endothelium. Int J Nanomedicine. 2017;12:7799. doi:10.2147/IJN.S14697829123394

 PubMed Web of Science ®Google Scholar

Mukhopadhyay P, Maity S, Mandal S, Chakraborti AS, Prajapati A, Kundu P. Preparation, characterization and in vivo evaluation of pH sensitive, safe quercetin-succinylated chitosan-alginate core-shell-corona nanoparticle for diabetes treatment. Carbohydr Polym. 2018;182:42–51. doi:10.1016/j.carbpol.2017.10.09829279124

 PubMed Web of Science ®Google Scholar

Chitkara D, Nikalaje SK, Mittal A, Chand M, Kumar N. Development of quercetin nanoformulation and in vivo evaluation using streptozotocin induced diabetic rat model. Drug Deliv Transl Res. 2012;2(2):112–123. doi:10.1007/s13346-012-0063-525786720

 PubMed Web of Science ®Google Scholar

Schwingel TE, Klein CP, Nicoletti NF, et al. Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice. Naunyn Schmiedebergs Arch Pharmacol. 2014;387(9):837–848. doi:10.1007/s00210-014-0994-024908156

 PubMed Web of Science ®Google Scholar

Alam MM, Abdullah K, Singh BR, Naqvi AH, Naseem I. Ameliorative effect of quercetin nanorods on diabetic mice: mechanistic and therapeutic strategies. RSC Adv. 2016;6(60):55092–55103. doi:10.1039/C6RA04821H

 Web of Science ®Google Scholar

Li L, Sheng X, Zhao S, et al. Nanoparticle-encapsulated emodin decreases diabetic neuropathic pain probably via a mechanism involving P2X3 receptor in the dorsal root ganglia. Purinergic Signal. 2017;13(4):559–568. doi:10.1007/s11302-017-9583-228840511

 PubMed Web of Science ®Google Scholar

Lu K, Xie S, Han S, et al. Preparation of a nano emodin transfersome and study on its anti-obesity mechanism in adipose tissue of diet-induced obese rats. J Transl Med. 2014;12(1):72. doi:10.1186/1479-5876-12-7224641917

 PubMedGoogle Scholar

Ravichandran R. Studies on gymnemic acids nanoparticulate formulations against diabetes mellitus. Int J Biomed Clin Eng. 2012;1(2):1–12. doi:10.4018/IJBCE

 Google Scholar

Wang J, Tan J, Luo J, et al. Enhancement of scutellarin oral delivery efficacy by vitamin B12-modified amphiphilic chitosan derivatives to treat type II diabetes induced-retinopathy. J Nanobiotechnology. 2017;15(1):18. doi:10.1186/s12951-017-0305-228249594

 PubMedGoogle Scholar

Yücel Ç, Karatoprak GŞ, Aktaş Y. Nanoliposomal resveratrol as a novel approach to treatment of diabetes mellitus. J Nanosci Nanotechnol. 2018;18(6):3856–3864. doi:10.1166/jnn.2018.1524729442719

 PubMed Web of Science ®Google Scholar

Shahraki A, Bahadorikhalili S, Hashemzaei M, et al. Resveratrol nano-capsule as an efficient tool for blood pressure regulation: a study on metabolic syndrome induced mice. Biosci Biotechnol Res Commun. 2017;10(4):623–630. doi:10.21786/bbrc/10.4/4

 Google Scholar

Das S, Roy P, Pal R, Auddy RG, Chakraborti AS, Mukherjee A. Engineered silybin nanoparticles educe efficient control in experimental diabetes. PLoS One. 2014;9(7):e101818. doi:10.1371/journal.pone.010181824991800

 PubMed Web of Science ®Google Scholar

Ahangarpour A, Oroojan AA, Khorsandi L, Kouchak M, Badavi M. Solid lipid nanoparticles of myricitrin have antioxidant and antidiabetic effects on streptozotocin-nicotinamide-induced diabetic model and myotube cell of male mouse. Oxid Med Cell Longev. 2018;2018. doi:10.1155/2018/7496936

 PubMed Web of Science ®Google Scholar

Barwal I, Sood A, Sharma M, Singh B, Yadav SC. Development of stevioside pluronic-F-68 copolymer based PLA-nanoparticles as an antidiabetic nanomedicine. Colloids Surf B. 2013;101:510–516. doi:10.1016/j.colsurfb.2012.07.005

 PubMed Web of Science ®Google Scholar

Paul D, Dey TK, Mukherjee S, Ghosh M, Dhar P. Comparative prophylactic effects of α-eleostearic acid rich nano and conventional emulsions in induced diabetic rats. J Food Sci Technol. 2014;51(9):1724–1736. doi:10.1007/s13197-014-1257-225190828

 PubMed Web of Science ®Google Scholar