Liposome-Derived Nanosystems for the Treatment of Behavioral and Neurodegenerative Diseases: The Promise of Niosomes, Transfersomes, and Ethosomes for Increased Brain Drug Bioavailability

Abstract

Psychiatric and neurodegenerative disorders are amongst the most prevalent and debilitating diseases, but current treatments either have low success rates, greatly due to the low permeability of the blood-brain barrier, and/or are connected to severe side effects. Hence, new strategies are extremely important, and here is where liposome-derived nanosystems come in. Niosomes, transfersomes, and ethosomes are nanometric vesicular structures that allow drug encapsulation, protecting them from degradation, and increasing their solubility, permeability, brain targeting, and bioavailability. This review highlighted the great potential of these nanosystems for the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, bipolar disorder, anxiety, and depression. Studies regarding the encapsulation of synthetic and natural-derived molecules in these systems, for intravenous, oral, transdermal, or intranasal administration, have led to an increased brain bioavailability when compared to conventional pharmaceutical forms. Moreover, the developed formulations proved to have neuroprotective, anti-inflammatory, and antioxidant effects, including brain neurotransmitter level restoration and brain oxidative status improvement, and improved locomotor activity or enhancement of recognition and working memories in animal models. Hence, albeit being relatively new technologies, niosomes, transfersomes, and ethosomes have already proven to increase the brain bioavailability of psychoactive drugs, leading to increased effectiveness and decreased side effects, showing promise as future therapeutics.

Keywords: Alzheimer’s disease; Parkinson’s; anxiety; brain bioavailability; depression; ethosomes; intranasal; niosomes; schizophrenia; transfersomes.

Figure 1

Schematic representation of high-incidence brain disorders and limitations of current treatments (produced with Biorender).

Figure 2

Schematic representation of liposome-derived vesicular nanosystems, namely ethosomes, transfersomes, and niosomes, and their respective composition and advantages in drug delivery (produced with Biorender). IN—intranasal; IV—intravenous; TD—transdermal.

Figure 3

(A) Representation of the composition of the developed insulin chitosan-coated transfersomes (left), and optical fluorescence imaging (right) of insulin uptake by several organs after intranasal administration of a drug suspension (FITC-INS) or the developed chitosan-coated transfersomes (FITC-CTI); (B–E) in vivo pharmacodynamic studies’ results involving the Morris water maze test (and pre-treatment with streptozotocin), in terms of escape latency time (B), swimming speed (C), distance traveled (D), and time spent in the target zone (E), after intranasal administration of the developed insulin chitosan-coated transfersomes (CTI), compared to the negative (CON) and positive (STZ) controls, intranasal drug suspension (INS), intranasal-uncoated transfersomes with no drug (TRA), or intranasal-uncoated transfersomes with the drug (TI); # p < 0.05 when compared to the control group; * p < 0.05, ** p < 0.005, *** p < 0.0005 when compared to the control group).adapted from Nojoki et al. [108], and reproduced with permission from Elsevier (Creative Commons CC BY 4.0 license).

Figure 4

(A,B) Transmission electron microscopy micrographs of the developed rasagiline transfersomes; (C) in vitro drug release profiles of the developed rasagiline transfersomes (F12), transfersomal in situ gels (G1, G2, and G3, with different polymer ratios), and drug dispersion; (D) brain drug concentration vs. time curve after intranasal administration of the optimized rasagiline in situ gel, and intravenous administration of a drug solution; (E,F) histopathological photomicrographs of rat nasal mucosa belonging to an untreated control group (E) and after intranasal administration of the optimized rasagiline transfersomal in situ gel (F) (hematoxylin and eosin staining); adapted from ElShagea et al. [109], and reproduced with permission from MDPI (Creative Commons CC BY 4.0 license).

Figure 5

(A,B) Transmission electron microscopy images of blank niosomes (A) and rivastigmine and N-Acetyl cysteine loaded niosomes (B); (C) cumulative nasal drug permeation of the developed niosomes (RIV + NAC-loaded niosomes) and drug solution (free RIV + NAC solution); (D) hemolysis percentage of the developed niosomes (RIV + NAC-loaded niosomes) and drug solution (free RIV + NAC); (E) in vivo pharmacokinetics after intranasal administration of the niosomes (RIV + NAC-loaded niosomes (IN)), intravenous administration of the niosomes (RIV + NAC-loaded niosomes (IV)), intranasal administration of a drug solution (free RIV + NAC solution (IN)), and intravenous administration of a drug solution (free RIV + NAC solution (IV)); adapted from Kulkarni et al. [113], and reproduced with permission from Elsevier (license number 5631891480781).

Figure 6

(A) Schematic representation of the developed carnosine-loaded niosomes, with potential application in brain targeting for the treatment of neurodegeneration-related molecular mechanisms, and applied assays; (B) in vitro anti-aggregation assay results, with estimation of anti-fibril formation effects of free and encapsulated carnosine (CARNIO); (C) in silico study of carnosine’s (and aminoguanidine’s) interaction with bovine serum albumin; ## p < 0.01, ### p < 0.001, when compared to positive control; $ p < 0.05, $$ p < 0.01, when compared to aminoguanidine 5 mM; adapted from Moulahoum et al. [114], and reproduced with permission from Elsevier (license number 5631900280594).