Journal
JOURNAL OF CONTROLLED RELEASE
Volume 258, Issue -, Pages 22-33Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2017.05.001
Keywords
Trigeminal nerve; Brain; Lymphatic system; Facial intradermal brain-targeted delivery; Mystacial pad; Intranasal injection; Schwann cell; Blood-brain barrier; Rat; Perineurium; Epineurium; Perivascular spaces; Neurons
Funding
- National Natural Science Foundation of China [81302726, 81603036, 81360195, 81301982, 81571392, 81272160]
- Natural Science Foundation of Zhejiang Province [LY17H170001]
- Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents
- 151 Talent Project of Zhejiang Province
- Key Support of High Level Talent Innovation and Technology Project of Wenzhou
- Wenzhou Bureau of Science and Technology [Y20160083, Y20160078]
- 551 talent project of Wenzhou
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Although intranasal delivery bypasses the blood-brain barrier (BBB), the anatomical location of the olfactory mucosa and respiratory airflow interference lead to less brain-targeted drug delivery. In addition to intranasal delivery, evidence indicates that facial intradermal injection might be a novel strategy for bypassing the BBB via the trigeminal nerve (TN). The hypothesis was verified by pharmacokinetic evaluation, nasal injury, lymphatic vessels inhibition and immunohistochemistry. Intradermal injection into the rat mystacial pad (i.d.) elevated the brain sub-areas and trigeminal Evans Blue (EB) concentrations, C-max and AUC((0-t)). I.d. also increased them in brain sub-areas beyond those of intranasal (i.n.) and intravenous injection (i.v.), especially the pons varolii and the medulla oblongata (sub-areas associated with TN). I.d. injection increased the brain drug targeting efficiency, brain direct transport percentage and brain bioavailability of EB while i.n. injection altered them slightly. Trigeminal transection and nasal injury reduced trigeminal EB with i.d. administration. Trigeminal perineurium, epineurium, perivascular spaces, neurons and Schwann cells were involved in the EB brain-targeted delivery. The lymphatic system mediated EB diffusion from the mystacial pad to the nasal mucosa and the brain. Thus, facial intradermal injection might be a promising strategy for brain-targeting delivery, bypassing the BBB via the trigeminal substructures.
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