Enhanced Delivery of Neuroactive Drugs via Nasal Delivery with a Self-Healing Supramolecular Gel

Abstract

This paper reports the use of a self-assembling hydrogel as a delivery vehicle for the Parkinson's disease drug l-DOPA. Based on a two-component combination of an l-glutamine amide derivative and benzaldehyde, this gel has very soft rheological properties and self-healing characteristics. It is demonstrated that the gel can be formulated to encapsulate l-DOPA. These drug-loaded gels are characterized, and rapid release of the drug is obtained from the gel network. This drug-loaded hydrogel has appropriate rheological characteristics to be amenable for injection. This system is therefore tested as a vehicle for nasal delivery of neurologically-active drugs-a drug delivery strategy that can potentially avoid first pass liver metabolism and bypass the blood-brain barrier, hence enhancing brain uptake. In vitro tests indicate that the gel has biocompatibility with respect to nasal epithelial cells. Furthermore, animal studies demonstrate that the nasal delivery of a gel loaded with ³ H-labeled l-DOPA out-performed a simple intranasal l-DOPA solution. This is attributed to longer residence times of the gel in the nasal cavity resulting in increased blood and brain concentrations. It is demonstrated that the likely routes of brain penetration of intranasally-delivered l-DOPA gel involve the trigeminal and olfactory nerves connecting to other brain regions.

Keywords: drug delivery; hydrogel; neuroactive drugs, supramolecular gel.

Figure 1

Synthesis of gelator 1 by mixing a glutamine amide derivative and benzaldehyde in water, structure of l‐DOPA and advantages of the self‐assembling gelator approach for nasal delivery.

Figure 2

a,b) Rheological study of gel formed by compound 1 (0.46% w/v) in water showing a) response of storage and loss modulus (G′, blue and G″, orange) to strain and b) the shear viscosity over time. At 200 s, a large strain is applied to the sample, which was then left to recover its gel‐like characteristics—this process took 40 s. c) (Left) SEM image of hydrogel formed from 1 loaded 1:1 with l‐DOPA, (right) TEM image of hydrogel formed from 1 loaded 1:1 with l‐DOPA. d) Release of l‐DOPA in vitro from the hydrogel formed by 1 loaded with l‐DOPA (0.8 x 10^–3 m).

Figure 3

Cytotoxicity of hydrogel and l‐DOPA loaded hydrogel in human nasal septum tumour RPMI 2650 cells. a) Cells were incubated with culture medium containing up to 10% l‐DOPA loading gel and l‐DOPA solution at the equivalent concentrations (up to 480 x 10^–6 m) for 24 and 48 h. b) Cells were treated with various concentration of hydrogel, Tween 80 and CTAB (up to 0.35 mg mL⁻¹) for 24 and 48 h. Data are expressed as mean ± SD, n = 5. Cytotoxicity was assessed by the standard MTT assay.

Figure 4

Uptake of [³H]l‐DOPA formulated in hydrogel or in solution in a) brain, b) nasal cavity, c) blood, and d) liver up to 1 h post intranasal administration. At the experimental end points, whole body perfusion with 0.9% saline was performed and studied tissues were harvested and proceeded for liquid scintillation counting. Results are expressed as %ID per tissue. Data are expressed as mean ± SD, n = 3. Statistical significance is indicated in comparison between each mode at the same time‐point. *p < 0.05, **0.01 < p < 0.05; ***p < 0.01 (one‐way ANOVA).

Figure 5

Brain distribution of [³H]l‐DOPA hydrogel at 10 min post intranasal administration. a) Dorsal view of the mouse brain and dissection guidance of different brain segments, the olfactory bulbs (OB), the cerebrum (CB 1&2), the brain stem (BS), cerebellum (CE), spinal cord (SP), and trigeminal nerves (TN). b) % of [³H]l‐DOPA uptake in different brain segments. At the experimental end points, whole body perfusion with 0.9% saline was performed and studied tissues were dissected and proceeded for liquid scintillation counting. Results are expressed as % uptake normalised to total [³H]l‐DOPA detected in these collected tissues. Data are expressed as mean ± SD, n = 3.