Nanodrugs: pharmacokinetics and safety

Figures & data

Table 1 Targeted delivery of nanoparticles

Targeting approaches	Outcomes	References
Transcellular transport
Cellular internalization	Caveolar-mediated endocytosis (<60 nm)	^Citation3,Citation10
	Clathrin-mediated endocytosis (<120 nm)	^Citation3,Citation10
Receptor-mediated endocytosis	Interaction of biomolecules coupled with nanoparticles by receptors on cellular surface	^Citation11,Citation12
Permeation enhancer	Perturbation of intracellular lipids by fatty acids	^Citation15
Paracellular transport
Bioadhesive polymers	Reversible tight junction opening and enhanced membrane permeability	^Citation16
Chelators	Reversible tight junction opening and enhanced membrane permeability	^Citation17
Others
Enhanced permeability and retention (EPR) effects	Accumulation in solid tumor	^Citation31
Conjugation with antibodies, proteins, peptides, and polysaccharides	Specific delivery to target tissues	^Citation18
Coating with uncharged hydrophilic materials	Improved stability and transport in mucus Avoidance of opsonization	^Citation14
Particle size control to avoid mucociliary clearance	High retention in lung tissue	^Citation22

Table 2 Nanodrugs and their biopharmaceutical characteristics

	Formulation system	Route	Observed pharmacokinetics/pharmacodynamics in vivo	References
Dendrimers
Doxorubicin	Polylysine dendrimer	IV	Prolonged systemic exposure Enhanced accumulation in tumor tissues	^Citation30
Flurbiprofen	Poly(amidoamine) dendrimer	IV	High distribution and retention in site of inflammation	^Citation32
Methotrexate	PEGylated polylysine dendrimer	IV	Prolonged systemic exposure	^Citation33
	Lactoferrin-conjugated dendrimer	IV	Enhanced accumulation in lung	^Citation34
Piroxicam	Poly(amidoamine) dendrimer	IV	Prolonged systemic exposure	^Citation35
Engineered nanoparticles
Carbendazim	Nanocrystals	Oral	Improved oral bioavailability	^Citation41
Cilostazol	Nanocrystals	Oral	Improved oral bioavailability	^Citation42
Curcumin	Nanocrystals	Oral	Improved oral bioavailability	^Citation43
Danazol	Nanocrystals	Oral	Improved oral bioavailability	^Citation44
Diclofenac	SoluMatrix™ fine particle technology	Oral	Faster absorption and prompt pain relief	^Citation51
Fenofibrate	Nanocrystals	Oral	Improved oral bioavailability	^Citation45
Indomethacin	SoluMatrix fine particle technology	Oral	Faster absorption	^Citation52
Megestrol acetate	Nanocrystals	Oral	Improved oral bioavailability	^Citation46
Nitrendipine	Nanocrystals	Oral	Improved oral bioavailability	^Citation47
Nobiletin	Nanosized amorphous particles	Oral	Improved oral bioavailability and hepatoprotection	^Citation48
Tranilast	Nanocrystals	Oral	Improved oral bioavailability and rapid absorption	^Citation49
	Inhalable nanocrystalline powders	Pulmonary	Enhanced anti-inflammatory effects in lung	^Citation50
Lipid nanosystems
Emulsion
Cinnarizine	Self-emulsifying drug delivery system	Oral	Improved oral bioavailability	^Citation56
Coenzyme Q10	Solid self-emulsifying drug delivery system	Oral	Improved oral bioavailability	^Citation57
Cyclosporin A	Self-emulsifying drug delivery system	Oral	Improved oral bioavailability with low variability	^Citation58
	Inhalable dry emulsions	Pulmonary	Enhanced anti-inflammatory effects in lung	^Citation19
Halofantrine	Self-emulsifying drug delivery system	Oral	Improved oral bioavailability	^Citation59
Simvastatin	Self-emulsifying drug delivery system	Oral	Improved oral bioavailability	^Citation60
Liposomes
Amikacin	Liposome (Phospholipid/Chol)	IV	Extended half-life of the drug in vitreous	^Citation29
Amphotericin B	Liposome (PC/Chol/DSPG)	IV	Increased systemic exposure, decreased RES uptake	^Citation63
Cytarabine/daunorubicin	Liposome (DSPC/DSPG/Chol)	IV	Decreased clearance	^Citation67
Doxorubicin	Liposome, PEGylated liposome	IV	High distribution in neoplastic tissue	^Citation62
O-palmitoyl tilisolol	Liposome (PC/Chol)	IV	High distribution and retention in the vitreous	^Citation64
Paclitaxel	Liposome (PC/PG)	IV	Prolonged systemic exposure	^Citation65
Prednisolone	Liposome (PC/Chol/10% DSPE-PEG2000)	IV	Increased and prolonged systemic exposure	^Citation61
Solid lipid nanoparticles
Azidothymidine	Solid lipid nanoparticles	IV	Enhanced permeability and retention to brain	^Citation68
Clozapine	Solid lipid nanoparticles	IV	Increased systemic exposure, decreased clearance	^Citation69
Diclofenac Na	Solid-in-oil nanosuspensions	Dermal	Increased percutaneous absorption	^Citation70
Insulin	Lectin-modified solid lipid nanoparticles	Oral	Improved oral bioavailability	^Citation71
Lidocaine	Solid lipid nanoparticles	Dermal	Controlled dermal permeation and duration of action	^Citation72
Micelles
Camptothecin	Block copolymeric micelles	IV	Prolonged systemic exposure	^Citation73
Doxorubicin	Block copolymeric micelles	IV	Increased systemic exposure, decreased clearance	^Citation74
Paclitaxel	Block copolymeric micelles	IV	Increased systemic exposure, decreased clearance	^Citation75
Pilocarpine	Block copolymeric micelles	Ocular	Increased miotic activity	^Citation76
Tranilast	Self-micellizing solid dispersion	Oral	Improved oral bioavailability	^Citation77
Polymeric nanoparticles
Celecoxib	Ethyl cellulose/casein nanoparticles	Oral	Improved oral bioavailability	^Citation81
Clotrimazole/econazole	PLGA and alginate nanoparticles	Oral	Improved oral bioavailability	^Citation85
Docetaxel	PLA-PEG nanoparticles	IV	Extended half-life, enhanced antitumor effect	^Citation84
Doxorubicin	PLGA nanoparticles	IV, IP	Extended half-life, reduced distribution to heart	^Citation86
Glucagon	PLGA nanoparticles	Pulmonary	Extended half-life and enhanced bioavailability	^Citation87
Insulin	Hydrogel nanoparticles	Oral	Improved oral bioavailability	^Citation83
Paclitaxel	Albumin nanoparticles	IV	Low inter-/intrapatient variability, tumor targeting	^Citation79
Rifampicin	PLGA nanoparticles	Oral	Improved oral bioavailability	^Citation88
siRNA	Chitosan analog nanoparticles	Oral	Improved systemic distribution and gene silencing	^Citation82
VIP derivative	PLGA nanoparticles	Pulmonary	Enhanced anti-inflammatory effects	^Citation20

Abbreviations: Chol, cholesterol; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; DSPE, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine; DSPG, 1,2-distearoyl-sn-glycero-3-phosphoglycerol; IP, intraperitoneal; IV, intravenous; PC, phosphatidylcholine; PG, phosphatidylglycerol; PEG, polyethylene glycol; PLA, polylactic acid; PLGA, poly(lactic-co-glycolic acid); RES, reticuloendothelial system; siRNA, small interfering ribonucleic acid; VIP, vasoactive intestinal peptide.

Table 3 Biopharmaceutical and safety characteristics of nanodrugs

Type of nanodrugs	Biopharmaceutical properties	Safety
Dendrimers	Advantages	Advantages
	High membrane permeability	Low immunogenicity
	Controlled release	Disadvantages
	Specific dug delivery	Hemotoxicity
	High solubilization
	Disadvantages
	Limited dosage routes
Engineered nanoparticles	Advantages	Advantages
	Improved systemic exposure	Decreased gastric irritancy of NSAIDs
	High retention in mucosal layer	Disadvantages
	Several dosage routes available	Toxic risk due to high Cmax
	Disadvantages	Cytotoxic potential
	Low sustained releasing potency
Lipid nanosystems	Advantages	Advantages
	Biodegradable and metabolized	Low toxicity
	Prolonged systemic exposure	Low antigenicity
	Specific drug delivery	Disadvantages
	Accumulation in tumor tissues	Cytotoxicity depending on the surfactant used
	Disadvantages
	Rapid clearance due to RES uptake
	Limited dosage route
Micelles	Advantages	Advantages
	High membrane permeability	Low immunogenicity
	High solubilizing potency	Disadvantages
	Improved systemic exposure	Toxic risk due to high Cmax
	Disadvantages	Cytotoxicity depending on used surfactant
	Low sustained releasing potency
Polymeric nanoparticles	Advantages	Advantages
	Stable in vivo drug release	Low immunogenicity
	Long duration of action	Disadvantages
	Disadvantages	Need to be removed surgically for nondegradable polymers
	Need to avoid initial burst  Limited dosage route

Abbreviations: C_max, maximum concentration; NSAID, nonsteroidal anti-inflammatory drug.

Figure 1 Biopharmaceutical characteristics of self-micellizing solid dispersions.

Notes: (A) Dissolution profiles of tranilast formulations in acidic solution (pH 1.2). ■, crystalline tranilast; ○, self-micellizing solid dispersion. Data represent mean ± SE of three independent experiments. Transmission electron microscopic image (inset) shows the self-micellizing solid dispersion redispersed in distilled water. Bar represents 500 nm. (B) Systemic exposure of tranilast after oral administration of tranilast formulations in rats. ■, crystalline tranilast (10 mg/kg); ○, self-micellizing solid dispersion (10 mg-tranilast/kg). Data represent mean ± SE of four to six experiments. Reprinted from Onoue S, Kojo Y, Suzuki H, et al. Development of novel solid dispersion of tranilast using amphiphilic block copolymer for improved oral bioavailability. Int J Pharm. 452(1–2):220–226.77 © 2013 with permission from Elsevier.

Abbreviations: h, hours, min, minutes, SE, standard error; TL, tranilast.

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