Nanotoxicological profiles of clinically approved nanoplatforms

Nkanga, Christian Isalomboto

doi:10.1186/s43088-023-00458-6

Beni-Suef University Journal of Basic and Applied Sciences

Table 2 Summary of representative studies evaluating the biocompatibility and toxicity of some PLGA-based NPs

From: Nanotoxicological profiles of clinically approved nanoplatforms

Formulation composition	Preparation method	Dose (administration route)	Animal/cell type	Cell/tissue target	Biocompatibility-/toxicity-related outcomes	References
In vitro studies
Fluorescein amine-labelled PLGA mixed with ε-caprolactone–PEG copolymers	Nanoprecipitation technique–solvent evaporation	18–180 μg/mL	L929 cell line	Mouse fibroblasts	PLGA-based NPs exhibited no changes in fibroblasts morphology and confluent monolayer after 48-h incubation, while dendrimers led to altered morphology and detachment in a dose-dependent way	Do et al. [30]
Gold NPs-coated polydopamine-modified PLGA capsule hybrid	Double emulsion, solvent evaporation	10–1000 μg/mL	ECA-109 cell line	Human oesophageal cancer cell	No remarkable cytotoxicity: cell viability was same as the control cells treated with PBS over 24 h	Xi et al. [149]
Monomethoxy-PEG-PLGA-poly(L-lysine) NPs	One-step oil-in-water emulsion, solvent evaporation	10–1000 μM	RAW 264.7, Huh7 and L02 cells	Murine macrophage, human hepatic carcinoma and normal embryo liver cells	No effect on cell membrane integrity, protein synthesis and chromatin stability, except dose-dependent and time-dependent increase in the content of reactive oxygen species. No significant induction of inflammatory cytokines	He et al. [55]
folic-acid-grafted-PEG-PLGA NPs co-loaded with cisplatin and paclitaxel	One-step oil-in-water emulsion, solvent evaporation	0.01–1 mg/mL	New Zealand white rabbits’ blood; M109 and A549 cells	Rabbit erythrocyte, murine and human lung carcinoma cell	Drug-free NPs exhibited no overt cytotoxicity, haemolysis, blood clotting or complement activation	He et al. [53]
Amphotericin B-loaded PLGA NPs decorated with dimercaptosuccinic acid ligand	Water-in-oil emulsification, solvent evaporation	1.56–600 μg/mL	Human blood and peritoneal tissues	Erythrocyte and peritoneal macrophages	Drug-loaded NPs were less haemolytic than plain drug. NPs showed no cytotoxicity, while free drug was toxic	Souza et al. [130]
Biotin/lactobionic acid-modified PEG-PLGA-PEG NPs co-loaded with curcumin and 5-fluorouracil	Nanoprecipitation technique–solvent evaporation	50–800 μg/mL	Hep G2 and HL 7702 cells	Human hepatocytes and hepatoma cells	Unlike drug-loaded NPs, the blank NPs showed no overt cytotoxicity after 48 h of incubation	Ni et al. [97]
Didodecyldimethylammonium bromide (DMAB)-stabilized PLGA modified with polyvinyl alcohol (PVA) or PEG	One-step oil-in-water emulsion, solvent evaporation	0.5–1000 μg/mL	Caco-2 cell line	Human epithelial colorectal adenocarcinoma cells	DMAB-PLGA NPs modified with PVA or PEG showed no cytotoxicity, while unmodified NPs induced significant concentration-dependent necrosis, apoptosis and chromatin disturbance	Gossmann et al. [46]
PLGA-poly(3-hydroxybutyrate) nanocomposite extract	Needle-punching non-woven fabric synthesis catalysed by Zr(AcAc)₄	Not indicated	Fibroblast-like cell line L929	Mouse fibroblast	No cytotoxic or genotoxic effects were observed following 72 h of incubation	Krucinska et al. [73]
PLGA NPs loaded with TRITC-in-polyethyleneimine	Double emulsion, solvent evaporation	Not indicated	Male and female gametes	Sperms, oocytes	No distinct morphological, chromosomal abnormalities, transgenerational effects or genetic aberrations were observed	Kim et al. [70]
PLGA-(poly-L-orithine/fucoidan) core–shell NPs	One-step oil-in-water emulsion, solvent evaporation	5–100 µg/mL	MCF-10A cell line	Breast epithelium cells and rabbit blood cells	Cell morphology was unchanged, but proliferation pattern was affected in a time-dependent way. Haemolysis rates increased with NPs concentrations	Cai et al. [21]
PLGA NPs	Nanoprecipitation, solvent evaporation	0.1–0.4 mg/ml	Primary human myoblasts and myotubes	Skeletal tissues	PLGA NPs did not decrease cell viability, while liposomes and silica NPs showed concentration-dependent and time-dependent decrease in cell viability	Guglielmi et al. [49]
PEG-PLGA, PEG-poly(L-lactide) (PLA) and PEG-PLA-PEG NPs	One-step oil-in-water emulsion, solvent evaporation	0.05–1 mg/ml	Fibroblast-like cell line L-929 and human umbilical vein endothelial cell	Mouse fibroblasts, blood, human macrophages and human vascular endothelium	No significant cytotoxicity observed. Adverse effects of PEG-PLGA NPs on haemolysis and inflammatory cytokines release were the highest while PEG-PLA-PEG NPs’ were the lowest	Shen et al. [125]
PLGA NPs loaded with Chondroitinase ABC (ChABC)	Double emulsion, solvent evaporation	1500–6000 µg/mL	Olfactory ensheathing cells	Rat olfactory mucosa	Following 48 h of incubation, there were no significant differences between the control and NP-treated cell viability	Azizi et al. [11]
Chitosan-coated PLGA nanoparticles loaded with bevacizumab	One-step oil-in-water emulsion, solvent evaporation	Not reported	Fertilized fresh hen’s eggs	Hen’s egg chorioallantoic membrane	NPs formulation was non-irritant and tolerated to chorioallantoic membrane after	Pandit et al. [104]
Cell-penetrating peptides decorating DNA-loaded PLGA nanoparticles	Double emulsion-solvent evaporation method	0.075–1.2 mg/mL	A549 and Beas-2B cells	Lung tissues	After 24-h incubation of NPs with cells, there was no change in mitochondrial activity and membrane integrity In addition, the inflammatory response and levels of apoptosis were significantly lower, and there was no activation of caspase-3	Dos Reis et al. [32]
In vivo studies
Monomethoxy-PEG-PLGA-poly(L-lysine) NPs	One-step oil-in-water emulsion, solvent evaporation	10–1000 μM	Zebrafish embryos	Heart	No effect on embryonic heartbeat rate, malformation or survival. At extreme concentrations (> 500 μM), NPs induced reactive oxygen species production at early stage of embryonic development	He et al. [54]
PLGA-poly(3-hydroxybutyrate) nanocomposite bone implant	Needle-punching non-woven fabric synthesis catalysed by Zr(AcAc)₄	Surgical femur implantation	New Zealand breed male and female rabbits	Blood, RES organs, stomach, small and large intestine, testes, uterus, heart	The blood cells remained unchanged. No significant differences between enzymes values from the test and control groups following 180 days of implantation	Krucinska et al. [73]
Biotin/lactobionic acid-modified PEG-PLGA-PEG NP	Nanoprecipitation, solvent evaporation	200 mg/kg every 2 h (IV)	Female nude balb/c mice	Liver, spleen, kidneys, lunges and heart	No obvious signs of cellular or organ injury or inflammation were observed, and no death was recorded after injection of up to 2000 mg/kg in total	Ni et al. [97]
PLGA NPs loaded with TRITC-in-polyethyleneimine	Double emulsion-solvent evaporation method	Not indicated	ICR mice	Murine embryos	No influence on embryo development to the blastocyst	Kim et al. [70]
Amphotericin B-loaded PLGA and PLGA-PEG blend NPs	One-step oil-in-water emulsion, solvent evaporation	10 mg/kg/day (oral or IP)	Male Wistar rat	Liver, kidneys and blood cells	Biochemical and histopathological parameters remained unchanged after 7 days of treatment. Unlike the plain drug, NPs showed no blood cell damage	Moraes Moreira Carraro et al. [93]
Amphotericin B-loaded PLGA NPs decorated with dimercaptosuccinic acid ligand	Water-in-oil emulsification, solvent evaporation	6 or 30 mg/kg/day (IP)	Healthy balb/c or Swiss mice	Blood, peritoneal, bone marrow cells	No significant difference between the DNA from mice treated with NPs and PBS, while control (cyclophosphamide) caused DNA damage. NPs showed similar neutrophils, leucocytes and monocytes as PBS, unlike the plain drug	Souza et al. [130]
PLGA-(poly-l-orithine/fucoidan) core–shell NPs	One-step oil-in-water emulsion, solvent evaporation	300 mg/kg (IP)	SPF mice	Liver and kidney	NPs showed no significant differences with negative control in body weight and histological parameters. No death or apparent toxicity was observed	Cai et al. [21]
PEG-PLGA, PEG-poly(L-lactide) (PLA) and PEG-PLA-PEG NPs	One-step oil-in-water emulsion, solvent evaporation	0.05–1 mg/ml	Zebrafish embryos	Heart and yolk sac	The concentration-dependent adverse effects of PEG-PLGA NPs on embryo survival and growth were the highest, while PEG-PLA-PEGs were lowest	Shen et al. [125]
PLGA NPs and surface-modified PLGA chitosan NPs	One-step oil-in-water emulsion, solvent evaporation	12 mg/kg/day (oral)	F344 rats	Spleen, kidney, liver, lung, brain, intestine, heart	No significant histological changes seen in tested organs, except for intestine and liver. Body weight remained unchanged	Navarro et al. [96]
Doxorubicin-loaded PLGA nanoparticles coated with poloxamer 188	Double emulsion-solvent evaporation technique	0.15–0.22 mg/kg/day (IV)	Chinchilla rabbits	Blood, Spleen, kidney, liver, lung, brain, intestine, heart	PLGA NPs significantly lowered the haematological, cardiac and testicular toxicity of the drug, but dose-dependent functional and morphological abnormalities were observed	Pereverzeva et al. [111]
Cx43MP peptide loaded PLGA nanoparticles	Nanoprecipitation technique–solvent evaporation	10–500 µg/mL	Zebrafish embryo toxicity (ZET) model	Embryos	Zebrafish remained normal 144 h after fertilization with the NPs; no significant malformations or cytotoxicity were obvious	Bisht and Rupenthal [17]
PLGA nanoparticles	Sonication method	100 μg/ml	BALB/c mice	Mouse cortical neuronal tissue	PLGA nanoparticles greatly protected neuronal cells against the aggregation of amyloid β (Aβ) peptide and showed favourable impact on the expression of AD-related genes/proteins	Wu et al. [148]
PLGA and PEG-PLGA nanoparticles	Sonication, solvent evaporation	1–25 µM	BALB/c mice	Frontal cortex from pup brains	PLGA nanoparticles inhibited β-amyloid (Aβ) peptides aggregation and triggered the disassembly of their aggregates beyond physiological temperatures, protecting neurons against Aβ-mediated toxicity	Paul et al. [109]

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