Signaling hormone The single chain polypeptide of human growth

Signaling molecules called hormones are synthesized in body and areresponsible for regulation of metabolic networks through hormone receptors.

Thespecial secretory cells of secretory glands and some cells with other primaryfunctions produce these messenger molecules. After release of hormones into theinterstitial fluid, some of them that act on adjacent cells and cells far fromthe gland produced them are called paracrine and endocrine, respectively. Alsosome of them act on receptors of the cells produced them which are calledautocrine.  According to hormones chemical structure, they are classified to threemain groups including lipid derived, amino acid derived and peptide derivedhormones.

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Peptide hormones include small proteins like follicle stimulatinghormone and polypeptide chains such as oxytocin and antidiuretic hormone. Mostof 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 inlaboratory. Beside great effects of administration of them on patientssuffering from hormone insufficiency, there are some limitations like poorgastrointestinal adsorption, quite plasma half-life, and sensitivity togastrointestinal hormones digestion which resulted in frequent injection that turn lead to non-specific toxicity, increasecosts of treatment and renal failure 1.3.

         Peptidehormones delivery systems3.1.      Hydrogelsfor therapeutic applicationsHuman growth hormoneThe single chain polypeptide of human growth hormone is composed of191 amino acids which produced tertiary structure of four helices and twodisulfide bridges. Somatotroph cells within the lateral section of the anteriorpituitary produce growth hormone and secret 0.5 and 0.875 mg of protein per day2.

Two controlling systems composedof GH-releasing hormone and somatostatin are responsible for stimulation andinhibition of hGH secretion, respectively 3. Beside these two main controlling agents, some physiologicalparameters like sleep, hyperglycemia, exercise, dietary habits and etc. havestimulatory or inhibitory effects on hGH secretion {Alba-Roth, 1988 #3}. The first uses of pituitary glands extracted hGH was for treatingchildren with growth hormone deficiency (GHD). This disease is because ofisolate hormonal deficiency, central nervous tumor, pituitary hormonedeficiency and cranial irradiation. Beside valuable effects of hGH replacementtherapy for GHD treatment, this hormone is used for curing various pathologic conditionslike Turner syndrome, Chronic renal insufficiency, Prader–Willi syndrome,Short-bowel syndrome, and AIDS-associated weight loss or cachexia.

Injection isthe conventional way for administration of hGH 4. hGH must administrated subcutaneously daily or three times a weekBecause of its low plasma half-life which leads to lowering patients compliance 5. Although hGH replacement therapy is accepted by scientists as agood treating protocol, its uses is still limited because of need to dailyinjections, and there is great interesting toward new formulations and new waysof drug delivery which sustain release the hormone 6.  Various studies performedin order to develop an hGH delivery system with lowest initial burst, andhighest bioavailability and therapeutic effect 7, 8.

Nutropin Depot was the first form of hGH with long acting properties. Althoughonly one injection of this formula which was encapsulated hGH in poly(lactic acid-co-glycolicacid) (PLGA) microspheres {Johnson, 1996 #9} is sufficient for one month, the scale up process was high costand also inflammation around the injection site and acidic environmentgenerated by PLGA hydrolysis were inevitable 1.  Also the encapsulationprocess involve solvent evaporation step which always lead to proteindenaturation and aggregation  9, 10. Furthermore these systems have some other drawbacks includinghigh initial burst release and low loading efficiency 1. Alternatively, biodegradable and thermo sensitive hydrogels seemsgood delivery system for hormones. These compounds have high water content andsome special characteristic like thermo and PH dependent gelation.  Recently, the porous network of hydrogelswith ability of biological fluids absorption has attracted attentions to itselffor using as a good delivery system.   The inflammations of injection site reducebecause of soft nature of hydrogels.

Unfortunately hydrogel cannot be injectedand need surgical implantation which is inconvenient and costly. Injectablehydrogel with high mold ability, ease administration, and minimal invasivemanner in vivo delivery was designed to overcome this throwbackPoly(amino carbonate urethane)-based Hydrogels Phan and his coworkers synthesizedPEG-PACU-basedpH-/temperature-sensitive injectable hydrogel for sustain delivery of hGH andshowed that this formula biodegraded in 50weeks with no inflammation and only asingle injection effectively release hGH for 4 days 1. Also the cytotoxicity tests demonstrate the safety of hydrogelsfor in vivo uses. This way of drug delivery is a promising method for improvingprotein stability, patient compliance and burst release inhibition.  Poly methacrylic acid based polymersA copolymer composed of methacrylic acid (MMA) interlinked withpoly ethylene glycol chains is one of the most extensively used hydrogels fororal delivery of proteins 8.

 It is an anionic hydrogelwhich collapsed in gastric environment but remains swollen in intestinalenvironments. Pegylation of MAA enhanced mucoadhessive properties of hydrogeland resulted in more retention of hydrogel in small intestine10. The pKa of MMA is naturally aligns with gastrointestinal tract pHand after copolymerization with hydrophilic monomers like poly ethylene glycolor N-vinyl pyrrolidone are able to trigger pH dependent way of therapeuticproteins 11. The oral delivery of hGH using a hydrogel system of poly methacrylicacid-co-N-vinyl pyrrolidone was evaluated by Carr et al. It was demonstratedthat this formula is an efficient system for delivery of hGH to upper smallintestine because of good release at first ours of study. Also as no release ofhGH in gastric conditions did not achieved it conclude that P (MAA-co-NVP) microparticles 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 composedof negatively charged hGH, PAEU copolymer hydrogeland positively 2D-layered hydroxide nanoparticle (LDH) was developed in orderto 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 invitro 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 hGHwas studied.

This system which is called SABER is weight based dosing forsustain release of hGH for more than 7 days 15. Researchers, over the years, have defined hydrogels in manydifferent 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 ormore monomers. Another definition is that it is a polymeric material thatexhibits the ability to swell and retain a significant fraction of water withinits structure, but will not dissolve in water.

Hydrogels have receivedconsiderable attention in the past 50 years, due to their exceptional promisein wide range of applications. They possess also a degree of flexibility verysimilar to natural tissue due to their large water content.The ability of hydrogels to absorb water arises from hydrophilicfunctional groups attached to the polymeric backbone, while their resistance todissolution 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 replacedby synthetic hydrogels which has long service life, high capacity of waterabsorption, and high gel strength. Fortunately, synthetic polymers usually havewell-defined structures that can be modified to yield tailor able degradabilityand functionality.

Hydrogels can be synthesized from purely syntheticcomponents. Also, it is stable in the conditions of sharp and strongfluctuations of temperatures.Recently, hydrogels have been defined as two- or multi-componentsystems consisting of a three-dimensional network of polymer chains and waterthat fills the space between macromolecules. Depending on the properties of thepolymer (polymers) used, as well as on the nature and density of the networkjoints, such structures in an equilibrium can contain various amounts of water;typically in the swollen state, the mass fraction of water in a hydrogel ismuch higher than the mass fraction of polymer. In practice, to achieve highdegrees of swelling, it is common to use synthetic polymers that arewater-soluble when in non-cross-linked form.Hydrogels may be synthesized in a number of “classical” chemicalways. These include one-step procedures like polymerization and parallelcross-linking of multifunctional monomers, as well as multiple step proceduresinvolving synthesis of polymer molecules having reactive groups and theirsubsequent cross-linking, possibly also by reacting polymers with suitablecross-linking agents. The polymer engineer can design and synthesize polymernetworks with molecular-scale control over structure such as cross-linkingdensity and with tailored properties, such as biodegradation, mechanicalstrength, and chemical and biological response to stimuli.

Hydrogels used in drug delivery are usually formed outside of thebody and impregnated with drugs before placement of the hydrogeledrug complexin the body. A wide range of cross-linking strategies can be used, including UVphotopolymerization and various chemical cross-linking techniques. Suchcross-linking methods are useful only if toxic reagents can be completelyremoved prior to hydrogel implantation, which may be difficult to achievewithout also leaching loaded drug out of the hydrogel. The main disadvantage ofsuch approaches is that the preformed material must be implanted, since bulkhydrogels have a defined dimensionality and often high elasticity whichgenerally excludes their extrusion through a needle. The latter problem cansometimes be circumvented by making the preformed gel into micro- ornanoparticles. In some applications, the hydrogels can also be formed in situ(i.e.

in vivo), although one then has to consider the potential risks ofexposure to UV irradiation (and the need for additional equipment) or tocross-linking chemicals.Peptide hormones (TH) play an important role in the development ofhuman brain, by regulating the expression of specific genes. SelectiveAlzheimer’s disease indicator-1 (seladin-1) is a recently discovered gene withneuroprotective properties, which has been found to be down-regulated in brainregions affected by Alzheimer’s disease.

Seladin-1 has anti-apoptoticproperties mainly due to the inhibition of the activation of caspase 3.