Drug delivery system for active brain targeting - Artificial Cells, Cell Engineering and Therapy - page 417

A multi-component drug delivery system that closely mimics the secretory
granule, the lumen of which is composed of a crosslinked poly-anionic
condensed polymer network encapsulated within a lipid membrane, was studied
by Kiser et al. (2000). This lipid-coated hydrogel microparticle (microgel) was
triggered to release doxorubicin content by using electroporation. When the
lipid-coated microgels were electroporated in a saline solution, they swelled and
disrupted their bilayer coating over a period of several seconds and exchanged
doxorubicin with the external plasma saline over a period of several minutes.
17.3.4 Intranasal
Delivery of a drug to a required site in the body is an important application of a
drug delivery system. It thus becomes possible to increase drug efficacy and
decrease systemic adverse reactions. Direct administration of a drug to the
affected site is the simplest and surest method. However, when a drug is injected
in aqueous solution, its efficacy is quickly lost through dispersion from the site
of application, in many cases making it impossible to obtain sufficient effects.
Therefore, it is important to retain the drug at the affected site for the period
required for onset of drug efficacy. In particular, at sites where frequent
administration is difficult, it is essential to use a sustained release preparation
that can maintain required local drug concentration.
The olfactory region of the nasal passages has unique anatomic and
physiological attributes that provide both extracellular and intracellular pathways
into the CNS that bypass the BBB. Olfactory sensory neurons are the only first-
order neurons whose cell bodies are located in a distal epithelium. A direct
extracellular pathway between the nasal passages and the brain was first
conclusively demonstrated for horseradish peroxidase (HRP), a 40 kDa protein
tracer. Electron microscopy showed that intranasally administered HRP migrates
through open intercellular clefts of the olfactory epithelium to the olfactory bulbs
of mice, rats and squirrel monkeys within minutes after application. Conversely,
the intracellular pathway from the nasal passages to the brain has been
demonstrated most convincingly for the lectin conjugate wheatgerm agglutinin-
HRP (WGA-HRP). Additional support for the existence of a direct pathway
connecting a submucosal compartment in the nasal passages to brain interstitial
fluid or CSF has come from the demonstration that a substantial fraction of large
molecular weight molecules are cleared from the CNS directly into the deep
cervical lymph nodes, which receive afferent lymphatics from the nasal passages.
Recent studies have shown nerve growth factor, fibroblast growth factor-2,
insulin, vasoactive intestinal peptide and growth factor analogs are able to gain
access to or have effects in brain tissue or CSF following intranasal admini-
stration. However, the precise mechanisms underlying nose to brain transport
remain incompletely understood and have led to differing interpretations of
experimental evidence for CNS delivery by the nasal route. Nevertheless,