Abstract
The direct delivery of central nervous system (CNS) drugs into the brain after administration is an ideal concept due to its effectiveness and non-toxicity. However, the blood–brain barrier (BBB) prevents drugs from penetrating the capillary endothelial cells, blocking their entry into the brain. Thus, alternative approaches must be developed. The nasal cavity directly leads from the olfactory epithelium to the brain through the cribriform plate of the skull bone. Nose-to-brain drug delivery could solve the BBB-related repulsion problem. Recently, it has been revealed that insulin improved Alzheimer’s disease (AD)-related dementia. Several ongoing AD clinical trials investigate the use of intranasal insulin delivery. Related to the real trajectory, intranasal labeled-insulins demonstrated distribution into the brain not only along the olfactory nerve but also the trigeminal nerve. Nonetheless, intranasally administered insulin was delivered into the brain. Therefore, insulin conjugates with covalent or non-covalent cargos, such as AD or other CNS drugs, could potentially contribute to a promising strategy to cure CNS-related diseases. In this review, I will introduce the CNS drug delivery approach into the brain using nanodelivery strategies for insulin through transcellular routes based on receptor-mediated transcytosis or through paracellular routes based on escaping the tight junction at the olfactory epithelium.
Highlights
The blood–brain barrier (BBB) pharmacokinetically blocks the entry of therapeutic agents into the brain
Transcytosis, is suggested suggested that certain certain types of insulin insulin dependent respectively itit is that types of suggested that certain types of insulin transportation systems operate through passing the olfactory transportationsystems systemsoperate operatethrough throughpassing passingthe theolfactory olfactoryepithelium epithelium barrier
In vivo observations suggested that intranasal insulin could pass through the trigeminal nerve. It might be easier not for hydrophobic small molecular compounds but for insulin to pass through the trigeminal nerve perineuronal space than to cross the continuous and fenestrated endothelium of blood vessels from the basolateral to the apical cell membrane based on transcytosis at the lamina propria of the respiratory epithelium, if the trigeminal nerve perineuronal space is open to extracellular fluid, similar to how the conduit interstitially formed by the olfactory ensheathing cells surrounding the olfactory sensory neuron is open to cerebrospinal fluid (CSF)
Summary
The blood–brain barrier (BBB) pharmacokinetically blocks the entry of therapeutic agents into the brain. Carrier-mediated transport using arbitrary substrates with cargos could be a direct approach to bypass MDR1 and the tight junction-based physical boundary at the BBB [3]. RMT using arbitrary ligands with cargos could be a direct approach to bypass tight junction-based physical boundaries at the BBB [4]. Drug delivery strategies physicochemical properties, such as hydrophobicity or hydrophilicity, stability, and depend on features such as molecular size, physicochemical properties, such as hydrophobicity or affinity to intermedium molecules, such as transporters and receptors, or target molecules It is true hydrophilicity, enzymatic stability, and affinity to intermedium molecules, such as transporters and that direct methods to cross the BBB using carrier-mediated transport and RMT could be receptors, target molecules.
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