Table 1.

Some examples of new innovative nanomedicine systems for pre-clinical therapies against inflammatory disorders.

Nanocarrier	Active principle	Inflammatory lesion	Animal model	Treatment time	Tested doses and route of administration	Main results	Ref
Eudragit S100 polymeric NPs	Prednisolone	Healthy	Wistar Albino rats	Every 30mins, from 1h to 6h	5 mg/kg of NPs, oral administration	•Specific colon targeting with a lag time	[45]
Pegylated liposomes	Prednisolone	Renal ischemia and reperfusion injury	8-week-old male LEW/HanHsd rats	96h	10 mg/kg of NPs, intravenous (i.v.) injection	•Specific accumulation in inflamed kidney •Increase of anti-inflammatory macrophages recruitment •Decrease of MCP-1 mRNA production	[47]
Hyaluronic acid-coated solid lipid NPs	Prednisolone	Collagen-antibody induced model of arthritis in Freud’s adjuvant	6-week-old male DBA/1 mice	4 injections, once every three days	15 mg/kg of equivalent prednisolone each time, intra-articular injections	•Selective accumulation in inflamed tissue •Good therapeutic efficacy based on analysis of joints, pannus formation, bone preservation and reduction of pro-inflammatory cytokines	[170]
Nano-sized elastic niosomes	Prednisolone	Clove oil-induced severe ocular inflammation	Albino rabbits	Every 4h, 3 times a day, for 6 days	Equivalent to 500 μg of prednisolone (A or P) each time, ocular delivery	•Time for complete healing reduced to half •Significant decrease of intraocular pressure elevation	[50]
Polycaprolactone NPs dispersed in fibrin glue-based gel system	Methyl-prednisolone sodium succinate	Acute spinal cord injury	Male Wistar Albino rats	24h	Doses = N/A, topical and intraperitoneal administration	•Reduced damage on spinal cord •Decrease in caspase 3 and pro-inflammatory cytokines levels	[51]
Hyaluronic acid hydrogel-based hydroxyl-terminated polyamidoamine dendrimers	Dexamethasone	Corneal alkali burn model	8-week-old Lewis rats	24h, 72h, 7 days or 14 days	Equivalent to 1.76 mg /kg of Dex, subconjunctival injection	•1.6-fold better anti-inflammatory activity at 10-fold lower concentration than free drug in vitro • In vivo: corneal features improvements, and decrease in macrophage infiltration and pro-inflammatory cytokines production	[52]
Poly(ethylene glycol)-poly( ε­caprolactone) polymer micelles	Dexamethasone	Adjuvant arthritis model by mycobacteria inoculation in Freund’s adjuvant	6-8 weeks Wistar rats	4 injections of Dex, on days 14, 16, 18, 20 after arthritis induction	0.8 mg/kg of Dex, intravenous injection	•Paw swelling and erythema suppression •Down-regulation of pro-inflammatory cytokines •Protection of articular cartilage and bone from degradation and erosion	[53]
Spherical polymeric nanoconstructs	Dexamethasone	Dextran sodium sulfate-induced model of arthritis	8-week-old female C57Bl/6J mice	At day 2 after lesion: 6 consecutive treatments distributed until 16 days	5 mg/kg each time, i.v. injections	•Reduced weight loss and rectal bleeding •Reduced macrophage infiltration and pro-inflammatory cytokines production	[54]
Solid lipid NPs	Dexamethasone and Butyrate	Dextran sodium sulfate-induced model of arthritis	8-week-old male BALB/c mice	Daily treatment started from day 6 after lesion, for 3 days	0.1 mg/kg of dexamethasone and 4 mg/kg of Butyrate, oral administration	•Significant decrease of pro-inflammatory cytokines, more effectively at doses 10-fold lower than with free drugs	[55]
N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer NPs	Dexamethasone	Adjuvant-induced arthritis	Male Lewis rats	One injection, at day 14, 15, 16 or 17 after arthritis induction	10 mg/kg of dexamethasone, intravenous injection	•Better systemic bone quality and bone protection •Amelioration of joint inflammation	[56]
Dual pH- and time-dependant polymeric NPs composed of Eudragit FS30D and Eudragit RS100	Budesonide	Dextran sodium sulfate-induced model of colitis	7-week-old mice	2h, 6h, or 10h	0.5 mg/kg of drug (0.168 mg/kg of budesonide), oral administration	•Improved colon-specific drug targeting •Body characteristics improvement	[58]
PLGA NPs	Budesonide	Oxazolone-mediated experimental colitis	8 to 12-week-old BALB/c mice	18h	42 μg of NPs, oral administration	•Selective targeting at the site of inflammation	[60]
Phosphatidyl serine:phosphatidyl choline (3:7 mol/mol) liposomes	Recombinant mouse IL-10	12 weeks High Fat Diet-induced obesity and atherosclerosis	C57Bl/6 mice	One treatment after 12 weeks of diet	1 μg/mouse of equivalent rIL-10, intraperitoneal injection	•Significant decrease in visceral fat weight •Reduced size of adipocytes •Reduced IL-6 and TNF-α secretion, and level of alanine amino transferase (decreased liver injury)	[69]
Biodegradable polyester polymeric NPs made with core polymer I, II and PLGA-PEG-ColIV	Recombinant mouse IL-10	Zymosan A (0.2 mg/mouse)-induced peritonitis (1) and 12 weeks of Western Diet-induced atherosclerosis (2)	8 to 10-week-old female C57Bl/6J (1) and 8 to 10-week-old male Ldlr-/- (2)	4h treatment (1) and 1/week for 4 weeks (2)	100 or 500 ng/mouse of equivalent rIL-10 (1) and 5 μg of rIL-10/ i.v. injection (2)	•Improvement of fibrous cap thickness •Reduction of necrotic core area •Tempered inflammation in peritonitis with decrease in polymorphonuclear neutrophils infiltration •Better macrophage targeting ability	[70]
Poly(NIPAm-co-AMPS) NPs	Anti-inflammatory cell penetrating peptide KAFAK	Osteoarthritis model induced by removal of native aggrecan of cartilage explants and IL1β treatment	3-month-old bovine knee joints explants	One treatment after 2 days of culture	50 μg NPs, treatment on cartilage explants	•Specific targeting of inflamed joint tissues •Reduction of pro-inflammatory cytokines	[79]
NGPEGSS NPs system incorporating NIPAm, AMPS, BAC, and PEG polymers	Anti-inflammatory cell penetrating peptide KAFAK	Osteoarthritis model by removal of native aggrecan cartilage explants and IL1β treatment	3-month-old bovine knee joint explants	One treatment after 2 days of culture	50 μg NPs, treatment on cartilage explants	•Specific targeting of inflamed joint tissues •Significant suppression of IL-6 production on days 4,6 and 8	[81]
Chitosan/poly(γ-glutamic acid) NPs	Diclofenac	LPS-induced inflammation	In vitro human macrophages	24h, 48h	0.7 mg/mL, in vitro treatment	•Rapid internalization (within 3 hours) without toxicity below 0.7 mg/mL •Stimulation of production of prostaglandin E2 •Reduction of IL-6 production	[64]
Mannose-modified trimethyl chitosan-cysteine NPs	TNF-α siRNA	Acute hepatic injury induced by LPS and D-GaIN	Male Sprague-Dawley rats	2h	20 μg or 50 μg of equivalent TNF-α siRNA/kg, oral administration	•Effective TNF-α knockdown at low doses •Dramatic alleviation of inflammatory conditions in the liver (congested central vein, swollen, disarranged hepatocytes, and broken cytolemma)	[82]
Nanoemulsion formulation of cationic lipid DOTAP	TNF-α siRNA	LPS intranigral injection-induced Parkinson’s disease model	Male Sprague-Dawley rats	6h, 24h	1.5 mg/kg of NPs, intranasal administration	•Preferential concentration into the brain •Brain downregulation of TNF-α	[115]
Poly(ethylene glycol)-poly(caprolactone) polymer micelles conjugated with Tat cell-penetrating peptide and siRNA targeting TNF-α	TNF-α siRNA	transient middle cerebral artery occlusion model of cerebral ischemia-reperfusion injury	10-week-old Sprague-Dawley male rats	At 30 min after middle cerebral artery occlusion	Equivalent of 30 μg of siRNA, intranasal administration	•Transport of the drug to the brain directly across the nasal mucosa, without going through the BBB •Reduced infarcted area and better neurological scores •Significant suppression of TNF-α production	[84]
Dendrimers functionalized with cationic pyrrolidinium or morpholinium surface groups	TNF-α siRNA	LPS-induced acute lung inflammation model by intranasal administration of LPS	6 to 8-week-old female CD-1 mice	28h, 96h	Pre-treatment 24h before inflammation, with 2 mg/kg of eq. siRNA concentration, intranasal administration	•Specific targeting in macrophages •Major inhibition of TNF-α •Modulation of all other cytokines (strong anti-inflammatory effect)	[85]
Modified chitosan nano-carrier deploying folic acid, diethylethylamine and PEG groups	TNF-α siRNA	Collagen-antibody induced model of arthritis	8 to 12-week-old female DBA/1 mice	Treatment at day 1, 3, 5, 7 after induction of inflammation and sacrifice at day 10	4 intraperitoneal injections at 50 μg of siRNA each	•Significant decrease of inflammation observed by improved clinical scores and lower TNF-α concentration in inflamed tissues •Decrease in articular cartilage destruction and bone loss	[86]
Tuftsin/alginate NPs	IL-10 pDNA	Adjuvant arthritis model by inoculation with Mycobacterium butyricum in Freund’s adjuvant	Male Lewis rats	From 1h to 24h	Intraperitoneal injection at day 19 post-lesion of 3 mg of NPs	•Specific targeting of macrophages in inflamed paws •Continuous recruitment of M2 macrophages to inflamed tissues •Sustained local and systemic IL-10 expression	[90]
Hyaluronic acid/ polyetyleneimine NPs	IL-10 and IL-4 pDNAs	Intraperitoneal injection of Brewer-thioglycollate medium to recruit peritoneal macrophages	6 to 8-week-old C57Bl/6 mice	48h	2h post inflammation, intraperitoneal injection of 100 μg of equivalent pDNA	•Effective targeting of peritoneal macrophages over-expressing CD44 receptors •Significant increase of Arg/iNOS ratios and CD163 expression •Reduced level of TNF-α and IL-1β in peritoneal macrophages and fluid •Increased IL-10 and IL-4 expression	[91]
Hyaluronic acid/chitosan NPs	Cytokine response modifier A pDNA	Anterior cruciate ligament transection model of osteoarthritis	6 to 8-week-old Male Sprague-Dawley rats	3 injections, every 4 weeks starting 4 weeks after lesion	4 μg of NPs/rat each time, i.v. injections	•Significant inhibition of cartilage damage, synovial inflammation, and loss of type II collagen •Down regulation of IL-1β, MMP-3 and MMP-13 in synovial tissues	[48]
Mannose-functionalized dendrimeric NPs using polyamidoamine dendrimer	Liver X receptor (LXR) ligand T0901317	12 weeks of Western Diet to induce atherosclerosis	Ldlr-/- mice	Once per week for 4 weeks after the 12 weeks of diet	200 μg of NPs by i.v. injection	•Specific uptake by macrophages and not hepatocytes in atherosclerotic plaques •Increased expression of LXR target genes (ABCA1/ABCG1) •Enhanced cholesterol efflux •Significant reduction in atherosclerotic plaque progression, plaque necrosis, and plaque inflammation	[108]
Biodegradable diblock PLGA-b-PEG copolymer NPs	Liver X receptor (LXR) ligand GW3965	Zymosan A-induced peritonitis	Ldlr-/- mice	5h treatment (1) or over 2 weeks (2)	10 mg/kg of equivalent agonist 1h prior to Zymosan injection (1) or 6 injections of 10 mg/kg (2), i.v. injections	•Significantly more efficient than free drug for inducing LXR target gene expression and suppressing inflammatory factors •Reduction of CD68-positive macrophage content of plaques (by 50%)	[109]
Phospholipid-reconstituted ApoA-I peptide-derived synthetic HDL	Liver X receptor (LXR) ligand T0901317	Atherogenic diet for 14 weeks	8-week-old male ApoE-deficient mice	3 times a week for 6 weeks	30 mg/kg of NPs, which is equal to 1.5 mg/kg of ligands, i.v. injections	•Specific accumulation in plaque and plaque regression •Up-regulation of expression of ATP-binding cassette transporters and increased cholesterol efflux in macrophages	[110]
Raspberry-like core/satellite NPs with methyl violagen-functionalized polymeric NPs (core) and azobenzene (corona)	IL-1Ra antagonist protein	Healthy	8 to 10-week-old male Sprague-Dawley rats	One treatment	5 μg of cy7-labelled NPs, intra-articular injection	•Improved retention time due to prolong half-life time of IL-1Ra in the joint compared to soluble form	[77]
Oleic acid-incorporated liquid crystalline monoolein-based NPs	Tacrolimus (FK506)	Daily topical dose (1.5 mg) of Imiquimod on shaved back for 5 days to induce a skin inflammation (psoriasis)	8 to 11-week-old BALB/c mice	Once a day, for 7 days after inflammation induction	30 μg of equivalent Tacrolimus each time, topical administration	•Significant increase in the amount of drug permeated and retained •More efficient in the treatment of skin inflammation than Tacrolimus in propylene glycol	[111]
Positively charged PEP−PEG−PBG polymer micelles	FK506	Dry eye disease animal model by subcutaneous injection of scopolamine	6-week-old C57BL/6 mice	4 times a day for 5 days	Topical application of 30 μg of the formulation each time	•Significantly reduce apoptosis of corneal epithelium •Suppression of inflammatory-related factors (TNF-α, IL-6, MMP-9…)	[112]
PEGylated liposomes	FK506	Experimental autoimmune myocarditis model induced by immunization with porcine myosin	7-week-old male Lewis rats	Treatment on day 14 and 17, sacrificed on day 21	0.035 mg/kg, 0.17 mg/kg or 0.35 mg/kg of equivalent drug per treatment, i.v. injection	•Increased level of FK506 in both plasma and hearts •Suppression of pro-inflammatory cytokine expression such as TNF-α and IFNγ •Reduced inflammation and fibrosis in the myocardium	[113]
PEGylated liposomes	Cyclosporin A	Transient middle cerebral artery occlusion by 90 min brain ischemia induction, followed by 48h reperfusion	Male Wistar rats	5min after ischemia, for 48h	2.5 mg/kg of equivalent cyclosporin A, i.v. injection	•Significant recovery of the infarct size, brain oedema, and neurological activities compared to free drug •Inhibition of inflammatory responses including MPO activity and TNF-α levels	[114]
Omega-3 fatty acid rich flaxseed oil-based nanoemulsion system	Cyclosporin A	LPS model of neuroinflammation	Sprague-Dawley rats	9h	Pre-treatment 3h prior to inflammation, with 5 mg/kg of NPs, intranasal administration	•Higher uptake in major regions of the brain •Inhibition of pro-inflammatory cytokines	[115]
Silicon dioxide NPs	Mesalazine	5% dextran sodium sulphate-induced ulcerative colitis model	8 to 9-week-old male BALB/c mice	Once a day, for 7 days, sacrifice on day 8	100 mg/kg per day of NPs, oral administration	•Significant decrease of IL-6 and TNF-α cytokine production and MPO activity	[116]
Squalene-adenosine NPs	Tocopherol (VitE)	Endotoxemia model of inflammation induced by intraperitoneal injection of LPS	8 to 12-week-old Male C57BL/6 and female BALB/c mice	One treatment, 30 min after LPS injection	15 mg/kg SQAd NPs (5.5 mg/kg of equivalent adenosine) and 15 mg/kg VitE, intravenous injection	•Significant decrease in TNF-α and increase in IL-10 production •Significant reduction of MCP-1 and IL-6 in the lung and kidney •Mitigation of MDA levels •Improved survival rate and clinical scores in lethal LPS model	[129]