Signaling hormone The single chain polypeptide of human growth

Signaling molecules called hormones are synthesized in body and are
responsible for regulation of metabolic networks through hormone receptors. The
special secretory cells of secretory glands and some cells with other primary
functions produce these messenger molecules. After release of hormones into the
interstitial fluid, some of them that act on adjacent cells and cells far from
the gland produced them are called paracrine and endocrine, respectively. Also
some of them act on receptors of the cells produced them which are called
autocrine. 

According to hormones chemical structure, they are classified to three
main groups including lipid derived, amino acid derived and peptide derived
hormones. Peptide hormones include small proteins like follicle stimulating
hormone and polypeptide chains such as oxytocin and antidiuretic hormone. Most
of Peptide hormones have endocrine effects on metabolism of distance cells {Norman, 1997 #1}. Now days with respect to genetic engineering technologies,
various therapeutic proteins including different hormones are produced in
laboratory. Beside great effects of administration of them on patients
suffering from hormone insufficiency, there are some limitations like poor
gastrointestinal adsorption, quite plasma half-life, and sensitivity to
gastrointestinal hormones digestion which resulted in frequent injection that turn lead to non-specific toxicity, increase
costs of treatment and renal failure 1.

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3.         Peptide
hormones delivery systems

3.1.      Hydrogels
for therapeutic applications

Human growth hormone

The single chain polypeptide of human growth hormone is composed of
191 amino acids which produced tertiary structure of four helices and two
disulfide bridges. Somatotroph cells within the lateral section of the anterior
pituitary produce growth hormone and secret 0.5 and 0.875 mg of protein per day
2. Two controlling systems composed
of GH-releasing hormone and somatostatin are responsible for stimulation and
inhibition of hGH secretion, respectively 3. Beside these two main controlling agents, some physiological
parameters like sleep, hyperglycemia, exercise, dietary habits and etc. have
stimulatory or inhibitory effects on hGH secretion {Alba-Roth, 1988 #3}.

The first uses of pituitary glands extracted hGH was for treating
children with growth hormone deficiency (GHD). This disease is because of
isolate hormonal deficiency, central nervous tumor, pituitary hormone
deficiency and cranial irradiation. Beside valuable effects of hGH replacement
therapy for GHD treatment, this hormone is used for curing various pathologic conditions
like Turner syndrome, Chronic renal insufficiency, Prader–Willi syndrome,
Short-bowel syndrome, and AIDS-associated weight loss or cachexia. Injection is
the conventional way for administration of hGH 4. hGH must administrated subcutaneously daily or three times a week
Because of its low plasma half-life 
which leads to lowering patients compliance 5. Although hGH replacement therapy is accepted by scientists as a
good treating protocol, its uses is still limited because of need to daily
injections, and there is great interesting toward new formulations and new ways
of drug delivery which sustain release the hormone 6.  Various studies performed
in order to develop an hGH delivery system with lowest initial burst, and
highest bioavailability and therapeutic effect 7, 8.

Nutropin Depot was the first form of hGH with long acting properties. Although
only one injection of this formula which was encapsulated hGH in poly(lactic acid-co-glycolic
acid) (PLGA) microspheres {Johnson, 1996 #9} is sufficient for one month, the scale up process was high cost
and also inflammation around the injection site and acidic environment
generated by PLGA hydrolysis were inevitable 1.  Also the encapsulation
process involve solvent evaporation step which always lead to protein
denaturation and aggregation  9, 10. Furthermore these systems have some other drawbacks including
high initial burst release and low loading efficiency 1.

Alternatively, biodegradable and thermo sensitive hydrogels seems
good delivery system for hormones. These compounds have high water content and
some special characteristic like thermo and PH dependent gelation.  Recently, the porous network of hydrogels
with ability of biological fluids absorption has attracted attentions to itself
for using as a good delivery system.   The inflammations of injection site reduce
because of soft nature of hydrogels. Unfortunately hydrogel cannot be injected
and need surgical implantation which is inconvenient and costly. Injectable
hydrogel with high mold ability, ease administration, and minimal invasive
manner in vivo delivery was designed to overcome this throwback

Poly(amino carbonate urethane)-based Hydrogels

 Phan and his coworkers synthesized
PEG-PACU-based
pH-/temperature-sensitive injectable hydrogel for sustain delivery of hGH and
showed that this formula biodegraded in 50weeks with no inflammation and only a
single injection effectively release hGH for 4 days 1. Also the cytotoxicity tests demonstrate the safety of hydrogels
for in vivo uses. This way of drug delivery is a promising method for improving
protein stability, patient compliance and burst release inhibition. 

Poly methacrylic acid based polymers

A copolymer composed of methacrylic acid (MMA) interlinked with
poly ethylene glycol chains is one of the most extensively used hydrogels for
oral delivery of proteins 8.  It is an anionic hydrogel
which collapsed in gastric environment but remains swollen in intestinal
environments. Pegylation of MAA enhanced mucoadhessive properties of hydrogel
and resulted in more retention of hydrogel in small intestine10. The pKa of MMA is naturally aligns with gastrointestinal tract pH
and after copolymerization with hydrophilic monomers like poly ethylene glycol
or N-vinyl pyrrolidone are able to trigger pH dependent way of therapeutic
proteins 11.

The oral delivery of hGH using a hydrogel system of poly methacrylic
acid-co-N-vinyl pyrrolidone was evaluated by Carr et al. It was demonstrated
that this formula is an efficient system for delivery of hGH to upper small
intestine because of good release at first ours of study. Also as no release of
hGH in gastric conditions did not achieved it conclude that P (MAA-co-NVP) micro
particles are suitable carrier for delivery of high molecular weight drugs 12.

———–

The ability of blended mixture of poly (vinyl alcohol) (PVA) and poly(acrylic acid) (PAA)
in combination with collagen (C) and hyaluronic acid  in delivery of hGH was revealed by Cascone.
The hGH release was linear during the first 3 days fallowed by rapid release 13.  A delivery system composed
of negatively charged hGH, PAEU copolymer hydrogel
and positively 2D-layered hydroxide nanoparticle (LDH) was developed in order
to overcame the limitations like premature degradation and low half-life of hGH.
The releasing period of hGH using this hydrogel system reached to 13 days in
vitro and 5 days in vivo 14.

A newly developed system composed of sucrose acetate isobutyrate was combined with poly lactic acid and its potential in delivery of hGH
was studied. This system which is called SABER is weight based dosing for
sustain release of hGH for more than 7 days 15.

Researchers, over the years, have defined hydrogels in many
different ways. The most common of these is that hydrogel is a water-swollen,
and cross-linked polymeric network produced by the simple reaction of one or
more monomers. Another definition is that it is a polymeric material that
exhibits the ability to swell and retain a significant fraction of water within
its structure, but will not dissolve in water. Hydrogels have received
considerable attention in the past 50 years, due to their exceptional promise
in wide range of applications. They possess also a degree of flexibility very
similar to natural tissue due to their large water content.

The ability of hydrogels to absorb water arises from hydrophilic
functional groups attached to the polymeric backbone, while their resistance to
dissolution arises from cross-links between network chains. Many materials,
both naturally occurring and synthetic, fit the definition of hydrogels.

During last two decades, natural Hydrogels were gradually replaced
by synthetic hydrogels which has long service life, high capacity of water
absorption, and high gel strength. Fortunately, synthetic polymers usually have
well-defined structures that can be modified to yield tailor able degradability
and functionality. Hydrogels can be synthesized from purely synthetic
components. Also, it is stable in the conditions of sharp and strong
fluctuations of temperatures.

Recently, hydrogels have been defined as two- or multi-component
systems consisting of a three-dimensional network of polymer chains and water
that fills the space between macromolecules. Depending on the properties of the
polymer (polymers) used, as well as on the nature and density of the network
joints, such structures in an equilibrium can contain various amounts of water;
typically in the swollen state, the mass fraction of water in a hydrogel is
much higher than the mass fraction of polymer. In practice, to achieve high
degrees of swelling, it is common to use synthetic polymers that are
water-soluble when in non-cross-linked form.

Hydrogels may be synthesized in a number of “classical” chemical
ways. These include one-step procedures like polymerization and parallel
cross-linking of multifunctional monomers, as well as multiple step procedures
involving synthesis of polymer molecules having reactive groups and their
subsequent cross-linking, possibly also by reacting polymers with suitable
cross-linking agents. The polymer engineer can design and synthesize polymer
networks with molecular-scale control over structure such as cross-linking
density and with tailored properties, such as biodegradation, mechanical
strength, and chemical and biological response to stimuli.

Hydrogels used in drug delivery are usually formed outside of the
body and impregnated with drugs before placement of the hydrogeledrug complex
in the body. A wide range of cross-linking strategies can be used, including UV
photopolymerization and various chemical cross-linking techniques. Such
cross-linking methods are useful only if toxic reagents can be completely
removed prior to hydrogel implantation, which may be difficult to achieve
without also leaching loaded drug out of the hydrogel. The main disadvantage of
such approaches is that the preformed material must be implanted, since bulk
hydrogels have a defined dimensionality and often high elasticity which
generally excludes their extrusion through a needle. The latter problem can
sometimes be circumvented by making the preformed gel into micro- or
nanoparticles. In some applications, the hydrogels can also be formed in situ
(i.e. in vivo), although one then has to consider the potential risks of
exposure to UV irradiation (and the need for additional equipment) or to
cross-linking chemicals.

Peptide hormones (TH) play an important role in the development of
human brain, by regulating the expression of specific genes. Selective
Alzheimer’s disease indicator-1 (seladin-1) is a recently discovered gene with
neuroprotective properties, which has been found to be down-regulated in brain
regions affected by Alzheimer’s disease. Seladin-1 has anti-apoptotic
properties mainly due to the inhibition of the activation of caspase 3.