Therapeutic Potential of Thymoquinone and Its Nanoformulations in Pulmonary Injury: A Comprehensive Review

Figures & data

Figure 1 The molecular function of thymoquinone (TQ) pathways.

Abbreviations: Bcl2, B-cell lymphoma; Akt, protein kinase; SOD, superoxide dismutase; CAT, catalase; GPX, glutathione peroxidase; IL6-IL8, proinflammatory cytokines IL-6, IL-8.

Figure 2 The pharmacological function of thymoquinone (TQ) as an anti-inflammatory agent in the prevention of lung disease.

Abbreviations: TGF-β, transforming growth factor β1; NK, natural killer cell activity; IFN-γ, interferon-gamma.

Table 1 Types of Thymoquinone (TQ) Nano-Formulations and Their Biological Activities

Effects	Animal/Cells	Nanomaterial/Stabilizer	References
6-fold increase of oral bioavailability	Rats	Low-viscosity hydroxy-propylcellulose-SSL	[^Citation123]
Anticancer	Breast cancer cells (MDA-MB-231)	Poly lactic-co-glycolic acid (PLGA)	[^Citation85]
	Breast cancer cells (MCF-7 and T47D)	TQ-loaded liposomes	[^Citation86]
	Breast cancer cells (MCF-7)	TQ beta-cyclodextrin self-assembling NPs	[^Citation87]
	Breast cancer cells (MCF-7)	Poly lactic-co-glycolic acid (PLGA)	[^Citation88]
	Breast cancer cells (MCF-7)	TQ-chitosan	[^Citation89]
	Breast cancer cells (MDA-MB-231)	TQ-loaded nanostructured lipid carrier	[^Citation56]
	Breast cancer cells (MCF-7 and HBL-100)	Polyvinylpyrrolidone and polyethylene glycol (PEG)	[^Citation90]
	Breast cancer cells (MCF-7)	Gold niosomes	[^Citation92]
	Mice/solid Ehrlich carcinoma	Poly-N-acetyl glucosamine nanomatrix	[^Citation93]
	Breast cancer cells (MCF-7)	Pluronic polymer micelles (F127)	[^Citation124]
	4T1 tumor-bearing female BALB/c mice	Nanostructured lipid carrier (NLCs)	[^Citation94]
	Breast cancer cells (UACC-732 and MCF-7)	Poly lactic-co-glycolic acid PLGA- polyethylene glycol (PEG)	[^Citation91]
	Cervical cancer cells (HeLa)	Silica nanoparticles (NPs)	[^Citation125]
Antidiabetic	Rats	Polymeric nanocapsules	[^Citation98]
Anti-ulcer	Rats	TQ-loaded TQ- Nanostructured lipid carrier (NLCs)	[^Citation100]
Brain targeting efficiency	Rats	Chitosan nanoparticles (NPs)	[^Citation107]
Hepatoprotective	Rats	Solid lipid nanoparticles (SLNs)	[^Citation103]
	Rats	TQ-loaded Nanostructured lipid carrier (NLCs)	[^Citation104]
	Rats	Self-nanoemulsifying drug delivery system (SNEDDS)	[^Citation105]
Neuroprotective	Rats	PLGA-chitosan nanoparticles (NPs)	[^Citation108]
	Rats	TQ- mucoadhesive nanoemulsion (TQMNE)	[^Citation110]
	Rats	TQ-rich fraction nanoemulsion (TQRFNE)	[^Citation111]
Protects against 3-nitropropionic acid induced Huntington’s disease-like symptoms	Rats	Solid lipid nanoparticles (SLNs)	[^Citation113]
	Rats	TQ loaded solid lipid nanoparticles (SLNs)	[^Citation114]

Figure 3 Thymoquinone (TQ) nanoformulations’ bioavailability, pharmacokinetics, and pharmacodynamic prospects against lung diseases.

Nihei T, Suzuki H, Aoki A, et al. Development of a novel nanoparticle formulation of thymoquinone with a cold wet-milling system and its pharmacokinetic analysis. Int J Pharmaceut. 2016;511:455–461. doi:10.1016/j.ijpharm.2016.07.038

 PubMedGoogle Scholar

Ganea GM, Fakayode SO, Losso JN, van Nostrum CF, Sabliov CM, Warner IM. Delivery of phytochemical thymoquinone using molecular micelle modified poly (D, L lactide-co-glycolide) (PLGA) nanoparticles. Nanotechnology. 2010;21:285104. doi:10.1088/0957-4484/21/28/285104

 PubMed Web of Science ®Google Scholar

Odeh F, Ismail SI, Abu-Dahab R, Mahmoud IS, Al Bawab A. Thymoquinone in liposomes: a study of loading efficiency and biological activity towards breast cancer. Drug Deliv. 2012;19:371–377. doi:10.3109/10717544.2012.727500

 PubMed Web of Science ®Google Scholar

Abu-Dahab R, Odeh F, Ismail SI, Azzam H, Al Bawab A. Preparation, characterization and antiproliferative activity of thymoquinone-beta-cyclodextrin self-assembling nanoparticles. Pharmazie. 2013;68:939–944. doi:10.1691/ph.2013.3033

 PubMed Web of Science ®Google Scholar

Soni P, Kaur J, Tikoo K. Dual drug-loaded paclitaxel–thymoquinone nanoparticles for effective breast cancer therapy. J Nanopart Res. 2015;17:18. doi:10.1007/s11051-014-2821-4

 Web of Science ®Google Scholar

Dehghani H, Hashemi M, Entezari M, Mohsenifar A. The comparison of anticancer activity of thymoquinone and nanothymoquinone on human breast adenocarcinoma. Iran J Pharm Res. 2015;14:539–546. doi:10.1007/s11051-014-2821-4

 PubMed Web of Science ®Google Scholar

Barnawi J, Tran HB, Roscioli E, et al. Pro-phagocytic effects of thymoquinone on cigarette smoke-exposed macrophages occur by modulation of the sphingosine-1-phosphate signalling system. COPD. 2016;13:653–661. doi:10.3109/15412555.2016.1153614

 PubMedGoogle Scholar

Bhattacharya S, Ahir M, Patra P, et al. PEGylated-thymoquinone-nanoparticle mediated retardation of breast cancer cell migration by deregulation of cytoskeletal actin polymerization through miR-34a. Biomaterials. 2015;51:91–107. doi:10.1016/j.biomaterials.2015.01.007

 PubMed Web of Science ®Google Scholar

Rajput S, Puvvada N, Kumar BNP, et al. Overcoming akt induced therapeutic resistance in breast cancer through siRNA and thymoquinone encapsulated multilamellar gold niosomes. Mol Pharm. 2015;12:4214–4225. doi:10.1021/acs.molpharmaceut.5b00692

 PubMed Web of Science ®Google Scholar

El-Ashmawy NE, Khedr EG, Ebeid EZM, Salem ML, Zidan AA, Mosalam EM. Enhanced anticancer effect and reduced toxicity of doxorubicin in combination with thymoquinone released from poly- N -acetyl glucosamine nanomatrix in mice bearing solid Ehrlish carcinoma. Eur J Pharm Sci. 2017;109:525–532. doi:10.1016/j.ejps.2017.09.012

 PubMed Web of Science ®Google Scholar

Shaarani S, Hamid S, Mohd kaus N. The Influence of pluronic F68 and F127 nanocarrier on physicochemical properties, in vitro release, and antiproliferative activity of thymoquinone drug. Pharmacognosy Res. 2017;9:12–20. doi:10.4103/0974-8490.199774

 PubMed Web of Science ®Google Scholar

Ong YS, Saiful Yazan L, Ng WK, et al. Thymoquinone loaded in nanostructured lipid carrier showed enhanced anticancer activity in 4T1 tumor-bearing mice. Nanomedicine. 2018;13:1567–1582. doi:10.2217/nnm-2017-0322

 PubMedGoogle Scholar

Ahmad R, Kaus NHM, Hamid S. Synthesis and characterization of PLGA-PEG thymoquinone nanoparticles and its cytotoxicity effects in tamoxifen-resistant breast cancer cells. In: Pham PV editor. Cancer Biology and Advances in Treatment. Springer; 2018:65–82. doi:10.1007/5584_2018_302.

 Google Scholar

Khattabi AM, Talib WH, Alqdeimat DA. The effect of polymer length on the in vitro characteristics of a drug loaded and targeted silica nanoparticles. Saudi Pharmaceut J. 2018;26:1022–1026. doi:10.1016/j.jsps.2018.05.010

 PubMed Web of Science ®Google Scholar

Rani R, Dahiya S, Dhingra D, Dilbaghi N, Kim KH, Kumar S. Improvement of antihyperglycemic activity of nano-thymoquinone in rat model of type-2 diabetes. Chem Biol Interact. 2018;295:119–132. doi:10.1016/j.cbi.2018.02.006

 PubMed Web of Science ®Google Scholar

Abdelwahab SI, Sheikh BY, Taha MM, et al. Thymoquinone-loaded nanostructured lipid carriers: preparation, gastroprotection, in vitro toxicity, and pharmacokinetic properties after extravascular administration. Int J Nanomedicine. 2013;8:2163–2172. doi:10.2147/IJN.S44108

 PubMed Web of Science ®Google Scholar

Alam S, Khan ZI, Mustafa G, et al. Development and evaluation of thymoquinone-encapsulated chitosan nanoparticles for nose-to-brain targeting: a pharmacoscintigraphic study. Int J Nanomed. 2012;7:5705–5718. doi:10.2147/IJN.S35329

 PubMed Web of Science ®Google Scholar

Singh A, Ahmad I, Akhter S, et al. Nanocarrier based formulation of thymoquinone improves oral delivery: stability assessment, in vitro and in vivo studies. Colloids Surf B Biointerfaces. 2013;102:822–832. doi:10.1016/j.colsurfb.2012.08.038

 PubMed Web of Science ®Google Scholar

Elmowafy M, Samy A, Raslan MA, et al. Enhancement of bioavailability and pharmacodynamic effects of thymoquinone via nanostructured lipid carrier (NLC) formulation. AAPS PharmSciTech. 2016;17:663–672. doi:10.1208/s12249-015-0391-0

 PubMed Web of Science ®Google Scholar

Kalam MA, Raish M, Ahmed A, et al. Oral bioavailability enhancement and hepatoprotective effects of thymoquinone by self-nanoemulsifying drug delivery system. Mater Sci Eng C Mater Biol Appl. 2017;76:319–329. doi:10.1016/j.msec.2017.03.088

 PubMed Web of Science ®Google Scholar

Xiao XY, Zhu YX, Bu JY, Li GW, Zhou JH, Zhou SP. Evaluation of neuroprotective effect of thymoquinone nanoformulation in the rodent cerebral ischemia-reperfusion model. Biomed Res Int. 2016;2016:2571060. doi:10.1155/2016/2571060

 PubMed Web of Science ®Google Scholar

Ahmad N, Ahmad R, Alam MA, Samim M, Iqbal Z, Ahmad FJ. Quantification and evaluation of thymoquinone loaded mucoadhesive nanoemulsion for treatment of cerebral ischemia. Int J Biol Macromol. 2016;88:320–332. doi:10.1016/j.ijbiomac.2016.03.019

 PubMed Web of Science ®Google Scholar

Ismail N, Ismail M, Azmi NH, et al. Thymoquinone-rich fraction nanoemulsion (TQRFNE) decreases Aβ40 and Aβ42 levels by modulating APP processing, up-regulating IDE and LRP1, and down-regulating BACE1 and RAGE in response to high fat/cholesterol diet-induced rats. Biomed Pharmacother. 2017;95:780–788. doi:10.1016/j.biopha.2017.08.074

 PubMed Web of Science ®Google Scholar

Ramachandran S, Thangarajan S. A novel therapeutic application of solid lipid nanoparticles encapsulated thymoquinone (TQ-SLNs) on 3-nitroproponic acid induced Huntington’s disease-like symptoms in wistar rats. Chem Biol Interact. 2016;256:25–36. doi:10.1016/j.cbi.2016.05.020

 PubMed Web of Science ®Google Scholar

Ramachandran S, Thangarajan S. Thymoquinone loaded solid lipid nanoparticles counteracts 3-Nitropropionic acid induced motor impairments and neuroinflammation in rat model of Huntington’s disease. Metab Brain Dis. 2018;33:1459–1470. doi:10.1007/s11011-018-0252-0

 PubMedGoogle Scholar