Transcript the herpes lysine

ATUFA KAWAN
08-ARID-1773
Ph.D (ZOOLOGY)
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Dendrimers are polymeric molecules ,chemically synthesized
with well defined shape, size and nanoscopic physiochemical
properties reminiscent of the proteins.
These polymers are almost spherical shape tree having
diameters generally between 2 and 10 nm.
Dendrimers possess three distinguished architectural
components namely,
An initiator core
an interior of shells (generation)
an exterior (outermost layer), which often has terminal
functional groups (Figure.1).
This unique architecture makes dendrimers monodispersed
macromolecules compared to classical linear polymers.
Fig.1: Dendritic Structure
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Monodispersity: Homogenous, well defined molecular structure, without
individual large variations
Polyvalency: Quantity of reaction sites on outer side of dendrimers have
potential to form connection with various molecules of interest
Nanoscale Dimensions and Shapes: Nanoscale dimensions due to their well
organized synthesis strategy and size controllable Properties. Within
PAMAM dendrimer family when grown from generations 1-10 the
diameter of dendrimers with an ethylenediamine core increases from 1.1 to
12.4nm.The shape of dendrimers may vary with their generations PAMAM
dendrimers of low generation (G0-G3) and high generation (G4-G10) have
ellipsoidal and spherical shape.
Solubility: Surface end groups→ hydrophobic→non polar solvent
→hydrophilic→polar solvent
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PAMAM (Poly Amidoamine) Dendrimer
PAMAMOS (Polyamidoamine organosilicon) Dendrimer
PPI Dendrimer(Poly Propylene Imine)
Tecto Dendrimer
Chiral Dendrimer
Hybrid Dendrimers
Amphiphilic Dendrimers
Peptide Dendrimer
DIFFERENCES BETWEEN
DENDRIMER AND LINEAR POLYMER
Property
Dendrimers
Linear polymers
Structure
Compact, Globular
Not compact
Architecture
Regular
Irregular
Size
Certain
Uncertain
Shape
Spherical
Random coil
Aqueous solubility
High
Low
1.
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Divergent Synthesis
In this method dendrimer grow from inside(co re molecule) to
outside through Michael addition. Starting from a reactive
core, a generation is grown and then the new periphery of the
molecule is activated for reaction with more monomers.
Michael Addition:
(Go) with four
Alkylation of amine
functional core with
methyl acrylate
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ethylene
diamine
terminal
amine groups
Esters
Produce branched (G0) with
four OH surface groups
Reaction with
ethanolamine
In this way the dendrimer size. weight and no of end group
increased.
Divergent Synthesis
2. Convergent Synthesis
In this method the dendrimer grow from outside to
inward.
Ist Step: The surface unit links together to form a large
wedge
2nd Step: The large surface units attached to the
multifunctional core unit
Convergent Synthesis
INTERACTIONS BETWEEN DENDRIMERS
AND DRUG MOLECULES
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Simple Encapsulation
The ellipsoidal or spheroidal shape, empty internal cavities
(hydrophobic properties, nitrogen or oxygen atoms) and open nature
of the architecture of dendrimers make it possible to directly
encapsulate guest molecules into macromolecules interior.
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Electrostatic Interaction
Dendrimers have functional groups on surface(such as such as
amine groups and carboxyl groups which are involved in enhancing
the solubility of hydrophobic drugs by electrostatic interaction(Fig.
2).
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Covalent Conjugation
The presence of large numbers of functional groups on the surface of
dendrimers make them suitable for covalent conjugation of
numerous drugs with relevant functional groups. Dendrimers have
been conjugated to various biologically active molecules such as
drugs, antibodies, sugar moieties and lipids.
Figure 2. Potential strategies for interactions between
dendrimers and drug molecules (A) electrostatic
interactions or covalent conjugate, and (B) simple
encapsulation.
Inflow & outflow of lacrimal fluids
2. Efficient naso-lacrimal drainage
3. Dilution with tears
4. Corneal barriers
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Non-corneal absorption:
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Penetration across sclera & conjunctiva into intra ocular
tissues.
Non productive: because penetrated drug is absorbed by
general circulation.
Corneal absorption:
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Outer epithelium: rate limiting barrier for lipophilic and
hydrophilic molecules.
Trans cellular transport: transport between corneal epithelium
and stroma
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Robinson et al., 2011 suggested the use of bioadhesive
polymers, such as poly (acrylic) acids, to improve drug
delivery and release by optimizing contact with the absorbing
area in order to prolong residence time and decrease dosage
frequency. Dendrimers like poly (amido amine) (PAMAM) are
used, which are liquid or semi-solid polymers and have several
amine carboxylic and hydroxyl surface groups which increases
with the generation number(G0, G1, G2, and so on).
Because of this unique architecture, PAMAM dendrimers, are
able to solubilize strongly and poorly water-soluble drugs into
their inner zones containing cascading tiers of branch cells
with radial connectivity to the initiator core and an exterior or
surface region of terminal moieties. So, greater possibilities
can be explored by using dendrimers as ophthalmic drug
delivery vehicles.
Vandamme and Brobeck, 2005 have reported the development
of using PAMAM dendrimers as ophthalmic vehicles in ocular
delivery systems. Pilocarpine nitrate and tropicamide were
employed as model drugs, respectively.
 The eye drops containing PAMAM dendrimers were also
found to have a prolongation of miotic activity.
 The authors explained that the increased availability of
Pilocarpine nitrate and tropicamide might be due to:
1) The host–guest relationship between dendrimers and drug
molecules, which induced slower release of these drugs
encapsulated in dendrimers’ interior cavities
2) And the bioadhesive properties of PAMAM dendrimers,
which can be explained by the structure, shape, and surface
functional groups of dendrimers.
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Ocular neovascularization is essential for normal eye
development but another main cause of blindness
when it is not well controlled. The most effective
angiogenic
factor
involved
in
ocular
neovascularization is vascular endothelial growth
factor (VEGF). A sense oligonucleotide named ODN1 was reported to have potent anti-VEGF activity.
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Wimmer et al., 2002 designed and synthesized lipid–
lysine dendrimers in an attempt to improve the
delivery of ODN-1 into the nuclei of retinal cells.
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TDDS can provide a steady drug blood concentration and thus
avoid peaks and valleys in the drug plasma levels, which occur
with traditional dosing, such as oral administration.
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However, transdermal delivery of drugs is limited due to the
slow rate of transdermal delivery, chiefly attributable to the
barrier functions of skin.
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The outer layer of the skin which is served as the first line of
defense, is composed of closely packed dead cells formed by
epidermal differentiation and cornification.
The most common method to improve drug penetration
through the skin is to use transdermal enhancers.
 Barry and coworkers describe the mechanisms by which
enhancers effect skin permeability:
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1.
Hydration
Water content of the stratum corneum is around 15 to 20%.
Additional water within stratum corneum could alter the
permeant solubility by swelling and opening of sratum
corneum.Hydration can be increased by occlusion with plastic
films.oils,waxes as components of ointments and water-in-oil
emulsions that prevent transepidermal water loss and oil-inwater emulsions that donate water.
2. Lipid Disruption by Chemical Enhancers
Azone,alcohols, dimethyl sulfoxide (DMSO) and fatty acids
have been shown to increase permeability by forming
permeable pores within lipids domains that provide less
resistance to polar molecules. These enhancer compounds
consist of a polar head group with a long alkyl chain and are
more effective for hydrophilic and lipophilic permeants.
3. Interaction with keratin
Urea, dimethyl sulfoxide interact with keratin in the
corneocytes. Barry suggested that these molecules may also
modify Peptide/ Protein material in the lipid bilayer domain to
enhance permeability.
4. Electrical Methods
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Iontophoresis
Driving charge molecules into skin by a small direct
current approximately 0.5 mA/cm2).
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Electroporation
Application of short micro to milli second electrical
pulses of approximately 100-1000 v/cm to create
transient aqueous pores.
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Numerous reports have been published describing the use of aminoterminated PAMAM or PPI dendrimers as non-viral gene transfer
agents, enhancing the transfection of DNA by endocytosis and,
ultimately reach into the cell nucleus by endosomal escape
mechanisms
proton sponge effect
The proton sponge effect is mediated by agents with a high
buffering capacity and the flexibility to swell when protonated.
Protonation, induces an extensive inflow of ions and water into the
endosomal environment which subsequently leads to rupture of the
endosomal membrane and release of the entrapped components.
Tertiary amine groups that contain a hydrophobic chain, have been
shown to accumulate in endosomes which have an acidic pH and
become detergents upon protonation resulting in disruption of the
membrane.
Fig.3.Dendrimers in GeneTransfection
Fig. 4. An artistic representation depicting the proton sponge hypothesis. The low
pH in endosomal environment leads to protonation of the entrapped agents with a
high buffering capacity. Protonation leads to inflow of H+ and Cl− and water into
the endosomes, resulting in osmotic swelling and endosome rupture.
3. Fusion in the endosomal membrane
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Destabilization of the endosomal membrane by
fusogenic peptides.
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Haemagluttinin which is a peptide of Influenza
virus coat act as fusogenic agent that is converted
from anionic hydrophilic coat at PH 7.4 to a
hydrophobic helical confirmation at acidic endosomal
PH. This α- helical lead to fusion of viral membrane
into cellular membrane.
4.Dendrimers as Nano- Drugs
Sulfonated
naphthyl group
Poly lysine
Useful antiviral
drug against Herpes
Simplex virus
Prevent and reduce
transmission of
HIV and STD
PAMAM
Dendrimers
nanocarriers
Inhibit cell adsorption
Viral replication
By interfering with
reverse transcriptase
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Silva JR, N.P., Menachof F.P., Chorilli, M. 2012. Dendrimers as potential platform in
nanotechnology-based drug delivery systems.IOSR Journal of Pharmacy, 2:23-30.
Garg T, Singh O, Arora S and Murthy RSR.Dendrimer a novel scaffold for drug delivery. IJPSR.
2011;7:211-220.
Jain A, Dubey S, Kaushik A and Kumar AT. Dendrimer: a complete drug carrier. IJPSR
2010;1(4):38-52.
Biricova V and Laznickova A.Dendrimers: Analytical characterization and applications. Bioorg
Chem. 2009;37:185–192.
Heather A.E. Benson. 2005. Trasndermal Drug Delivery: Penetration Enhancement Techniques.
2:22-33.
Heather A.E. Benson. 2005. Trasndermal Drug Delivery: Penetration Enhancement Techniques.
2:22-33.
Vandamme, TH.F. and L. Brobeck, 2005. Poly(amidoamine) dendrimers as ophthalmic vehicles for
ocular delivery of pilocarpine nitrate and tropicamide. Journal of Controlled Release, 102: 23-38.
Sonke, S. and D.A. Tomalia, 2005. Dendrimers in biomedical application reflection on the field.
Advanced Drug Delivery Reviews, 57: 2106-2129.
JPVC, Li H. 2003. Efficacy of dendrimer-mediated angiostatin and TIMP-2 gene delivery on
inhibition of tumor growth and angiogenesis: In vitro and in vivo studies. Int J Cancer 105:419–429.
Barbara K and Maria B: Review Dendrimers: properties and applications. Acta Biochimica Polonica
2001; 48:199–208.