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Intranasal, siRNA Delivery to the Brain by TAT/MGF Tagged PEGylated Chitosan Nanoparticles.

Malhotra M, Tomaro-Duchesneau C, Saha S, Prakash S - J Pharm (Cairo) (2013)

Bottom Line: The currently used delivery strategies such as implantation of catheters, intracarotid infusions, surgeries, and chemotherapies are invasive in nature and pose a greater risk of postsurgical complications, which can have fatal side effects.The results indicate that 0.5 mg/kg of siRNA is delivered successfully to the hippocampus, thalamus, hypothalamus, and Purkinje cells in the cerebellum after 4 hrs of post intranasal delivery.The results indicate maximum delivery to the brain in comparison to other tissues with no cellular toxic effects.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Technology and Cell Therapy Research Laboratory, Departments of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street, Room 311, Lyman Duff Medical Building, Montreal, QC, Canada H3A 2B4.

ABSTRACT
Neurodegeneration is characterized by progressive loss of structure and function of neurons. Several therapeutic methods and drugs are available to alleviate the symptoms of these diseases. The currently used delivery strategies such as implantation of catheters, intracarotid infusions, surgeries, and chemotherapies are invasive in nature and pose a greater risk of postsurgical complications, which can have fatal side effects. The current study utilizes a peptide (TAT and MGF) tagged PEGylated chitosan nanoparticle formulation for siRNA delivery, administered intranasally, which can bypass the blood brain barrier. The study investigates the optimal dose, duration, biodistribution, and toxicity, of the nanoparticle-siRNA formulation, in-vivo. The results indicate that 0.5 mg/kg of siRNA is delivered successfully to the hippocampus, thalamus, hypothalamus, and Purkinje cells in the cerebellum after 4 hrs of post intranasal delivery. The results indicate maximum delivery to the brain in comparison to other tissues with no cellular toxic effects. This study shows the potential of peptide-tagged PEGylated chitosan nanoparticles to be delivered intranasally and target brain tissue for the treatment of neurological disorders.

No MeSH data available.


Related in: MedlinePlus

(a) Histopathological images of organ tissues collected 4 h following administration of the novel nanoparticle formulation containing biotin-siRNA dose at 0.5 mg/kg in animals, indicating biodistribution. The study confirmed maximum delivery of biotin-siRNA in the brain (cerebral cortex and cerebellum), with a lesser extent in the heart, kidney, liver, lungs, and stomach. The results of nanoparticle-based siRNA delivery on the left were compared to the untreated control animals on the right. (b) Quantitative analysis using Image J of the stained area in tissues from animals receiving scrambled biotin-siRNA dose, complexed in nanoparticles at 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, compared with the untreated control receiving 0.85% w/v NaCl. The graph shows a representative result of independent readings from two animals in each group (n = 2) mean ± s.d. ∗∗∗P < 0.01 was considered highly significant based on Tukey's post hoc analysis, when compared with other groups.
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fig4: (a) Histopathological images of organ tissues collected 4 h following administration of the novel nanoparticle formulation containing biotin-siRNA dose at 0.5 mg/kg in animals, indicating biodistribution. The study confirmed maximum delivery of biotin-siRNA in the brain (cerebral cortex and cerebellum), with a lesser extent in the heart, kidney, liver, lungs, and stomach. The results of nanoparticle-based siRNA delivery on the left were compared to the untreated control animals on the right. (b) Quantitative analysis using Image J of the stained area in tissues from animals receiving scrambled biotin-siRNA dose, complexed in nanoparticles at 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, compared with the untreated control receiving 0.85% w/v NaCl. The graph shows a representative result of independent readings from two animals in each group (n = 2) mean ± s.d. ∗∗∗P < 0.01 was considered highly significant based on Tukey's post hoc analysis, when compared with other groups.

Mentions: The biodistribution study was performed with animals receiving different concentrations of the biotin-siRNA/nanoparticle dose. The maximum biodistribution to other organs including brain was observed in animals that received 0.5 mg/kg of siRNA/nanoparticle dose. Figure 4(a) represents histopathological sections of tissues from different organs receiving 0.5 mg/kg of biotin-siRNA/nanoparticle dose (left column) compared to untreated control (right column), sacrificed after 4 hrs of dose administration. The staining in the brain tissue was highly significant with 0.5 mg/kg scrambled biotin-siRNA/nanoparticle dose in both cerebral cortex and cerebellum (P = 0.0001) and also with 0.25 mg/kg but only in the cerebral cortex (P = 0.006), as represented in Figure 4(b). The staining with biotin-siRNA/nanoparticle dose at 0.5 mg/kg was also observed to target heart sarcomeres (P < 0.01) with significance as compared to other dose concentrations, 0.25 mg/kg (P = 0.403), 1 mg/kg (P = 0.562), and 2 mg/kg (P = 0.999) (Figure 4(b)). Renal cells in the medulla region of the kidney and hepatic cells also showed brown-colored staining in the cells, with 0.5 mg/kg of scrambled biotin-siRNA/nanoparticle formulation (P = 0.0001), as compared to the untreated control (Figure 4(b)). The glandular cells of the stomach and alveoli in lungs showed no significant difference as compared with the untreated control. Among all the concentrations of different treatment doses tested, the highest staining was observed with 0.5 mg/kg of scrambled biotin-siRNA/nanoparticle formulation in the cerebral cortex and cerebellum (P < 0.01), when compared with staining in other organs, except the heart.


Intranasal, siRNA Delivery to the Brain by TAT/MGF Tagged PEGylated Chitosan Nanoparticles.

Malhotra M, Tomaro-Duchesneau C, Saha S, Prakash S - J Pharm (Cairo) (2013)

(a) Histopathological images of organ tissues collected 4 h following administration of the novel nanoparticle formulation containing biotin-siRNA dose at 0.5 mg/kg in animals, indicating biodistribution. The study confirmed maximum delivery of biotin-siRNA in the brain (cerebral cortex and cerebellum), with a lesser extent in the heart, kidney, liver, lungs, and stomach. The results of nanoparticle-based siRNA delivery on the left were compared to the untreated control animals on the right. (b) Quantitative analysis using Image J of the stained area in tissues from animals receiving scrambled biotin-siRNA dose, complexed in nanoparticles at 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, compared with the untreated control receiving 0.85% w/v NaCl. The graph shows a representative result of independent readings from two animals in each group (n = 2) mean ± s.d. ∗∗∗P < 0.01 was considered highly significant based on Tukey's post hoc analysis, when compared with other groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4590831&req=5

fig4: (a) Histopathological images of organ tissues collected 4 h following administration of the novel nanoparticle formulation containing biotin-siRNA dose at 0.5 mg/kg in animals, indicating biodistribution. The study confirmed maximum delivery of biotin-siRNA in the brain (cerebral cortex and cerebellum), with a lesser extent in the heart, kidney, liver, lungs, and stomach. The results of nanoparticle-based siRNA delivery on the left were compared to the untreated control animals on the right. (b) Quantitative analysis using Image J of the stained area in tissues from animals receiving scrambled biotin-siRNA dose, complexed in nanoparticles at 0.25 mg/kg, 0.5 mg/kg, 1 mg/kg, and 2 mg/kg, compared with the untreated control receiving 0.85% w/v NaCl. The graph shows a representative result of independent readings from two animals in each group (n = 2) mean ± s.d. ∗∗∗P < 0.01 was considered highly significant based on Tukey's post hoc analysis, when compared with other groups.
Mentions: The biodistribution study was performed with animals receiving different concentrations of the biotin-siRNA/nanoparticle dose. The maximum biodistribution to other organs including brain was observed in animals that received 0.5 mg/kg of siRNA/nanoparticle dose. Figure 4(a) represents histopathological sections of tissues from different organs receiving 0.5 mg/kg of biotin-siRNA/nanoparticle dose (left column) compared to untreated control (right column), sacrificed after 4 hrs of dose administration. The staining in the brain tissue was highly significant with 0.5 mg/kg scrambled biotin-siRNA/nanoparticle dose in both cerebral cortex and cerebellum (P = 0.0001) and also with 0.25 mg/kg but only in the cerebral cortex (P = 0.006), as represented in Figure 4(b). The staining with biotin-siRNA/nanoparticle dose at 0.5 mg/kg was also observed to target heart sarcomeres (P < 0.01) with significance as compared to other dose concentrations, 0.25 mg/kg (P = 0.403), 1 mg/kg (P = 0.562), and 2 mg/kg (P = 0.999) (Figure 4(b)). Renal cells in the medulla region of the kidney and hepatic cells also showed brown-colored staining in the cells, with 0.5 mg/kg of scrambled biotin-siRNA/nanoparticle formulation (P = 0.0001), as compared to the untreated control (Figure 4(b)). The glandular cells of the stomach and alveoli in lungs showed no significant difference as compared with the untreated control. Among all the concentrations of different treatment doses tested, the highest staining was observed with 0.5 mg/kg of scrambled biotin-siRNA/nanoparticle formulation in the cerebral cortex and cerebellum (P < 0.01), when compared with staining in other organs, except the heart.

Bottom Line: The currently used delivery strategies such as implantation of catheters, intracarotid infusions, surgeries, and chemotherapies are invasive in nature and pose a greater risk of postsurgical complications, which can have fatal side effects.The results indicate that 0.5 mg/kg of siRNA is delivered successfully to the hippocampus, thalamus, hypothalamus, and Purkinje cells in the cerebellum after 4 hrs of post intranasal delivery.The results indicate maximum delivery to the brain in comparison to other tissues with no cellular toxic effects.

View Article: PubMed Central - PubMed

Affiliation: Biomedical Technology and Cell Therapy Research Laboratory, Departments of Biomedical Engineering, Faculty of Medicine, McGill University, 3775 University Street, Room 311, Lyman Duff Medical Building, Montreal, QC, Canada H3A 2B4.

ABSTRACT
Neurodegeneration is characterized by progressive loss of structure and function of neurons. Several therapeutic methods and drugs are available to alleviate the symptoms of these diseases. The currently used delivery strategies such as implantation of catheters, intracarotid infusions, surgeries, and chemotherapies are invasive in nature and pose a greater risk of postsurgical complications, which can have fatal side effects. The current study utilizes a peptide (TAT and MGF) tagged PEGylated chitosan nanoparticle formulation for siRNA delivery, administered intranasally, which can bypass the blood brain barrier. The study investigates the optimal dose, duration, biodistribution, and toxicity, of the nanoparticle-siRNA formulation, in-vivo. The results indicate that 0.5 mg/kg of siRNA is delivered successfully to the hippocampus, thalamus, hypothalamus, and Purkinje cells in the cerebellum after 4 hrs of post intranasal delivery. The results indicate maximum delivery to the brain in comparison to other tissues with no cellular toxic effects. This study shows the potential of peptide-tagged PEGylated chitosan nanoparticles to be delivered intranasally and target brain tissue for the treatment of neurological disorders.

No MeSH data available.


Related in: MedlinePlus