Table 2.

Observed outcomes after in vivo administration of several AgNP formulations by different administration routes.

AgNPs Coating	Size (nm)	Dose (mg/kg BW)	Time of Exposure	Model	Observed Outcome	Ref
PVP	10–30	Daily i.p. of 0.25, 0.5, 1	9 d	Male Balb/C mice	Toxic damage in major organs at all doses (lung, liver, spleen, kidney, heart, brain, and testicles) Dose-dependent toxicity on the lung. Thickening of interstitial tissues and focal interstitial pneumonia (0.5 mg/kg BW). Significant interstitial pneumonia with massive cell infiltration and interstitial hemorrhage (1 mg/kg BW).	[127]
PVP	25	Final dose 0.02 using inhalation chamber	Exposure to 0.7 mg/m3 AgNPs for a half-hour every day until 45 days	Male C57BL/6 mice	Cell cycle arrest in the G2/M phase Upregulation of COX2/PGE2 intracrine pathway Accelerate lung cellular senescence Cause mild fibrosis.	[130]
PVP	50 and 200	3.75, 75, 150, 300 μg	3 and 21 d	Female Wistar rat	Dose-dependent toxicity. DNA double-strand breaks. Damage to alveolar macrophages and endothelial cell destruction Lung inflammation.	[40]
PVP and citrate	20, 60 and 100 nm	10 μg Ag/mouse	4 and 24 h	Male ICR mouse	IL-1β and neutrophils in BALF, lung inflammation but do not indicate if PVP- or citrate-AgNps produce it. Size-dependent toxicity for citrate-AgNPs.	[131]
Citrate	20 and 110 nm	0.5 mg AgNPs/kg BW	24 h	Sprague Dawley Rats	Size-dependent uptake and toxicity. Ion flux dysfunction, ROS production. Uptake-dependence produces cytoskeleton rearrangement, stiffening of mechanics, and cytoskeleton damage that softens the mechanical profile.	[44]
Citrate	20 and 110	Single n.a. 7.2 and 5.4 mg/m3	6 h	Male Sprague Dawley rats	Presence of silver in tissue macrophages obtained from BALF, 56 days post-exposure. AgNPs are predominantly localized within the lung’s terminal bronchial/alveolar duct junction region associated with extracellular matrix and within epithelial cells.	[128]
Citrate	20	o.a. 0.25	24 h	Male mice CBA/J, C57L/J, MRL/MpJ, NOD/ShiLtJ, NZB/BlNJ, NZO/HlLtJ, NZW/LacJ, PL/J, PWD/PhJ, PWK/PhJ, TALLYHO/JngJ, WSB/EiJ, BALB/cJ, BTBRT + tf/J, C3H/HeJ, C57BL/10J, DBA/2J, FVB/NJ, SJL/J, SM/J, SWR/J, 129S1/SvImJ, A/J, AKR/J, and C57BL/6J.	Strain and treatment-dependent in neutrophils in BALF with the exception of SWR/J, DBA/2J, and SM/J. Lung inflammation	[132]
Citrate	20 nm	Single IV 5	1, 3, and 5 d	Male Sprague Dawley rats	Time-dependent Ag accumulation in the lung. Ag+ accelerates the dissolution of citrate-AgNPs by MT overexpression.	[133]
Citrate, octreotide (OCT), and Citrate/ OCT/ alginate (ALG)	22.77 ± 1.1, 78.77 ± 2.3, and 155.99 ± 5.2 nm	Nebulization of 1.27 at a rate of 5 mL/h for 3d (10h/d)	3 d	Male and female Sprague Dawley rats	AgNPs surface modification with OCT and ALG favors AgNPs accumulation in the lung and enhances interaction with somatostatin receptors (SSRT)in tumor cell lines.	[134]
ND	14–15 nm	0.05, 0.12, and 0.38 mg/m3 (Low, medium, and high dose respectively) in an inhalation chamber	6 h/day, 5 days/week for 12 weeks	Male and female Sprague Dawley rats	Accumulation in greater quantity in the lung, and in a dose-dependent manner in the liver, kidney, blood, vessel, eye, and testicle. No effect on the brain High amounts of silver were maintained after 12 weeks in liver, vessel, and eyes	[101]
ND	18–19 nm	0.049, 0.133 o 0.515 mg/m3 (Low, medium, and high dose respectively) in a whole-body inhalation chamber	6 hours/day, 5 days/week for 13 weeks	Male and female Sprague Dawley rats	Accumulation in greater quantity in the lung, liver, vessel, kidney, brain, and olfactory bulb Accumulation in a dose-dependent manner 0.7, 1.8, and 4.3 μg silver/kg dry weight of tissue in blood	[99]
ND	15 nm	0.133 mg/m3	Laminar horizontal flow, ventilation exchange rate of 20 times/hr) for 6 hr	Female Fischer 344 rats	Accumulation in greater quantity in the lung, nasal cavities, lymph nodes associated with the lungs, and blood. Low in heart, liver, blood vessel, kidney, and brain. Recovery 7 days after exposure.	[125]
ND	18.1–19.6 nm	0.031, 0.082, 0.116 g/m3	6 h/day, 5 days/week for 4 weeks in a nose-only inhalation chamber	Male Sprague Dawley rats	Accumulation in lung with a recovery of half the day after 14.7, 6.4 and 1.6 μg silver/kg dry weight of tissue in blood, followed by a low elimination phase of 60 to 100 days	[126]
ND	20 and 200	IV single dose to the tail vein of 5	24 h, 7 and 28 d	Male Wistar rats	Time-dependent change in concentration of silver in the liver, spleen, kidneys, lungs, and the brain. The highest amount of silver in the lungs was observed after 7 days. Individual AgNPs and AgNPs cluster were found within lung macrophages attached to the alveolar wall and inside the interstitium. AgNPs accumulated in the cytoplasm, mitochondria, and nucleus.	[129]
ND	8–22	Daily i.p. of 0.01	36 d	female severe combined immunodeficient (SCID) mice	Apoptosis. Significant tumor growth decrease after 36 days of treatment. No toxicological effects studied.	[135]
ND	27.9–33.4 and 57.3–33.4	* More information in the paper	40 min	Rat (no defined strain or sex)	Neutrophil increase in BALF with a size and dose-dependent response. Lung inflammation.	[136]
ND	20 nm	i.i. 50 μg AgNPs/rat	7 and 28 d	Male Sprague Dawley rats	Lung parenchyma injury, alveolar collapse, parenchymal fibrosis. Partial recovery after 28d but persistence of inflammatory/fibrosis response.	[137]
ND	10–20	i.i. 200 μg per rat	(1) Once a day for 7 days (2) Single intratracheal instillation	Male Sprague Dawley rats	Enhancement of oxidative stress, mitochondrial dynamic imbalance. Thickening of the alveolar septa, accumulation of macrophages in the alveoli, formation of pulmonary bullae and pulmonary consolidation, the disintegration of the mitochondrial cristae, and swelling of the mitochondria.	[138]

BW = bodyweight; i.i. = intratracheal installation; i.p. = intraperitoneal injection; IV = intravenous injection; n.a. = nose aerosol; o.a. = oropharyngeal aspiration; * details of complete admininistration scheme could be consulted in reference [136].