ISSN: 0975-766X CODEN: IJPTFI Available through Online ... · drug delivery. It has been reported...

Rathore Priyanka* et al. /International Journal Of Pharmacy&Technology

IJPT | April-2012 | Vol. 4 | Issue No.1 | 1875-1888 Page 1875

ISSN: 0975-766X

CODEN: IJPTFI Available through Online Review Article

www.ijptonline.com AQUASOMES: A PROMISING NANOBIOPHARMACEUTICAL DRUG DELIVERY SYSTEM FOR

PROTEINS AND PEPTIDES Rathore Priyanka*,,,, Duggal Shipra, Swami Gaurav

Department of Pharmaceutical Sciences, C.T. Group of Institutes, Shahpur campus, Jalandhar, Punjab (India). Email: [email protected]

Received on 02-01-2012 Accepted on 16-01-2012

Abstract

Aquasomes are one of the recently developed nanobiopharmaceutical carrier system that are found as niche for

proteins and peptides and composed of three layered self assembled structure, comprised of a solid phase

nanocrystalline core coated with oligomeric film to which biochemically active molecules are adsorbed with or

without modification, which is the based upon nanotechnology, a scientific field devoted to the manipulation of

atoms and molecules to construct miniature structures for new molecular assemblies at the nanometer scale size.

Aquasomes contains the particle core composed of nanocrystalline calcium phosphate or ceramic diamond, and is

covered by a polyhydroxyl oligomeric film and are spherical 60-300 nm particle used for drug and antigen delivery.

Three types of core material are mainly used for producing aquasomes: tin oxide, nanocrystalline carbon ceramics

(diamonds) and brushite (calcium phosphate dehydrates). Calcium phosphate is the core of interest, owing to its

natural presence in the body. The brushite is unstable and converts to hydroxyapatite upon prolong storage. Therefore

Hydroxyapatite is a better core for the preparation of aquasomes. It is widely used for the preparation of implants for

drug delivery. It has been reported haemoglobin loaded aquasomes using hydroxyapatite core as potential artificial

oxygen carrying system. Properties like protection and preservation of fragile biological molecules, conformational

integrity, and surface exposure made it as a successful carrier system for bioactive molecules like peptides, proteins,

hormones, antigens and genes to specific sites. Thus aquasomes is one of the most prominent and latest lipid

technologies. As lipid formulations always produce a fine dispersion which is useful for increasing the solubility of



poorly water soluble drugs. The study methodology includes different formulations which are as follows: oil based

formulation, triglyceride, liposomes, niosomes, lipid emulsions, emulsome, hydrogel nanoparticles, aquasomes, solid

lipid nanopartciles, and nanostructure lipid carriers. The ability of target-specific nano- and microparticle to carry

therapeutic agents (such as drugs, genes, or proteins) is essential for the application of nanotechnology in modern

medicine.

Keywords: aquasomes, nanoparticles, nanocrystalline core, self assembling carrier system.

Introduction

Term Aquasomes meaning “water bodies” are the combination of biotechnology and nanotechnology. Aquasomes are

nanoparticulate carrier sysytem mainly composed of three layered self assembled structures, comprised of a solid

phase nanocrystalline core substance coated with ploymeric or oligomeric film to which biochemically active

molecules such as protiens and peptides are adsorbed with or without any modifictaion. aquasomes being called as

“bodies of water”, their water like properties protect and preserve sensitive or labile biological molecules, and thus

maintaining conformational integrity as well as high degree of surface exposure are exploited in targeting of bio-

active molecules like peptide and protein hormones, antigens and genes to specific sites. Carbohydrates plays

important role acting as natural stabilizer, stabilization efficiency includes fungal spores producing alkaloid stabilized

by solution rich in sucrose1 and molecular denaturation indused by desication prevented by certain disaccharides2.

These carbohydrate stabilize nanoparticles of ceramic are known as “aquasomes” which was first developed by Nir

Kossovsky. The pharmacologically active molecule incorporated by following method co-polymerization, diffusion

or adsorption to carbohydrate surface of pre-formed nanoparticles. This three layerered structure involving self

assembled mainly by non-colvent bonds. Principle of “self assembly of macromolecule” is governed by three

physiochemical process 3,4 as discussed in this paper. Bioavailability is defined as the rate and extend to which the

active form of drug is absorbed from the drug product in the blood stream and becomes available at the target site.

Poor bioavailability is indicative of poor aqueous solubility, slow dissolution rate in biological fluids, poor stability of



dissolved drug at physiological pH, poor permeation through biomembrane, extensive presystemic metabolism. There

are three major approaches to overcome the problems associated to bioavailability.

A) Pharmaceutics approach: Involves modification of formulation, process of manufacturing or physiochemical

properties of the drug.

B) Pharmacokinetics of drug is modified by changing its chemical structure.

PHYSIOCHEMICAL PROCESS USED IN SYNTHESIS OF NANOPARTICULATE STRUCTURE

Array of covalently linked atoms generated with well defined composition connectivity and shape.

1. Covalent polymerization method used for preparing molecules with high molecular weight, low weight substance

allow to react with itself to produce molecule comprising of many covalently linked-monomers.

2. Self organizing systhesis depends upon weaker and less directional bonds such as ionic, covalent and vander waal

3. Molecular self assembly proceeds as following:

• Formation of intermediate structural complex through covalent synthesis.

• Formation of stable structure complex through ionic, hydrogen and vander waal bonding.

• Use of reapeted multiple copies for final assembling of non covalent connections between must be stable.

Targets

1. Aquasomes protect bio-active and labile molecules. Many other carriers like prodrugs and liposomes are being

utilized but these are prone to destructive interactions between drug and carrier in such case aquasomes proof to

be worthy carrier, oligomeric or carbohydrate coating prevents destructive denaturing interaction between drug

and solid carriers.

2. Aquasomes maintains molecular confirmation and optimum pharmacological activity. The active molecules

possess following qualities i.e. a unique three-dimensional conformation, a freedom of internal molecular

rearrangement induced by molecular interations and a freedom of bulk movement but proteins undergo

irreversible in aqueous state. In the aqueous state pH, temperature, solvents, salt cause denaturation5. In such case,



aquasomes with natural stabilizers like various polyhydroxy sugars act as dehydroprotectant maintains water like

state thereby preserves molecules in dry solid state and maintains conformational stability.

FORMULATION OF AQUASOMES

I. Principles of self assembly3,4

The self assembly of macromolecules in the aqueous environment, either for the purpose of creating smart

nanostructed materials or in the cource of naturally occurring biochemistry, is governed basically by three

physicochemical processes:

Interaction between charged groups

Dehydration effects

Structural stability

1. Interactions between Charged Groups:

� The interaction of charged group facilitates long range approach of self assembly sub units charge group also

plays a role in stabilizing tertiary structures of folded proteins.

� The intrinsic chemical groups or adsorbed ions from the biological milieu lend to most bilological and

synthetic surface a charge polarity. Most biochemically relevent molecules, in fact are ampoteric.

� The interactions of charged groups such as amino-, carboxyl-, sulfate-, and phosphate-groups, facilitate the

long range interaction of constituent subunits beginning at an intermolecular distance of around 15 nm, is the

necessary first phase of self assembly.

� With hydrophobic structures, long range forces may extend up to 25 nm. Charged groups also play a role in

stabilizing tertiary structures of folded proteins.

2. Hydrogen Bonding and Dehydration effects:

� Hydrogen bond helps in base pair matching and stabilization secondary protien structure such as alpha helices

and beta sheets.



� Molecular forming hydrogen bonds are hydrophilic and this confers a significant degree of organization to

surrounding water molecues.

� Hydrophobic molecules, which are incapable of forming hydrogen bond, their tendency to repel water helps to

organize the moiety to surrounding environment, organized water decreases level of entropy and is

thermodynamically unfavorable, the molecule dehydrate and get assembled.

3. Structural Stability:

� Structural stability of protein in biological environment determined by interaction between charged group and

Hydrogen bonds largely external to molecule and by van der waals forces largely internal to molecule

experienced by hydrophobic molecules, reponsible for hardness and softness of molecules, and maintenance

of internal secondary structures, provides sufficient softness, allows maintenance of conformation during self

assembly.

� Self assembly leads to altered biological activity, van der waals need to be buffered. In aquasomes, sugars

help in molecular plasticization.

� Van der waals forces, most often experienced by the reletively hydrophobic molecular regions that are shielde

from water, play a subtle but critical role in maintaining molecular conformation durimg self assembly.

� Van der waals forces lagely internal to the molecules also play a small but measurable role in the interaction

of polypeptides with carbohydrates and related plyhydroxyoligomers.

II. METHOD OF PREPARATION OF AQUASOMES 6,7,8,9,10

The general procedure consists of an inorganic core formation, which will be coated with lactose forming the

polyhydroeylated core that finally will be loaded by model drug.

The core is coated with a polyhydroxyl oligomeric film, and the coated particles are then allowed to adsorb a drug

or antigen. The final product consists of three layers: drug (or antigen), polybydroxyl oligomeric film, and the

nanocrystalline ceramic core.

IJPT | April-2012 | Vol. 4 | Issue No.1 | 1875

The aquasomes are prepared using the principle of self

preparation of core, coating of core, and immbolization of drug molecule.

Fig showing: syntheseis of aquasomes (brushite) colloidal precipitate or ceramic diamond.

1. Preparation of the core: The first step of aquasome prepar

of ceramic core preparation depends on the selection of the materials for core. These ceramic cores can be

fabricated by colloidal precipitation and sonication, inverted rnagnetron sputtering, plasma comdensation and other

processes. Ceramics materials were widely used as

ensure that any surface modification will have only a limited effect on the nature of the atoms below the surface

layer and thus the bulk properties of the ceramic will be preserved. The high

surface will exhibit high level of surface energy that will favor the binding of polyhydroxy oligomeric surface

film. Two ceramic cores that are most often used are diamond and calcium phosphate.

2. Carbohydrate coating: the second step involves coating by carbohydrates on the surface of ceramic cores. There

are number of processes to enable the carbohydrate (polyhydroxy oligomers) coating to adsorb epitaxially on to

the surface of the nano-crytalline ceramic cores. The

oligomer to a dispersion of meticulously cleaned ceramics in ultra pure water, sonication and then lyophilization to

promote the largely irreversible adsorption of carbohydrate on to the ceraminc surfa


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aquasomes are prepared using the principle of self-assembly, the aquasomes are prepared in three steps i.e.,

coating of core, and immbolization of drug molecule.

: syntheseis of aquasomes consists of fabricating a nanocrystaline core of a calcium phosphate

(brushite) colloidal precipitate or ceramic diamond.

: The first step of aquasome preparation is the fabrication of the

preparation depends on the selection of the materials for core. These ceramic cores can be


processes. Ceramics materials were widely used as coreand being crystalline, the high degree of order in ceramics


properties of the ceramic will be preserved. The high degree of order also ensures that the


film. Two ceramic cores that are most often used are diamond and calcium phosphate.

: the second step involves coating by carbohydrates on the surface of ceramic cores. There


crytalline ceramic cores. The processes generally entail the addition of polyhydroxy


promote the largely irreversible adsorption of carbohydrate on to the ceraminc surfa

* et al. /International Journal Of Pharmacy&Technology

Page 1880

assembly, the aquasomes are prepared in three steps i.e.,

consists of fabricating a nanocrystaline core of a calcium phosphate

ation is the fabrication of the ceramic core. The process

preparation depends on the selection of the materials for core. These ceramic cores can be


coreand being crystalline, the high degree of order in ceramics


degree of order also ensures that the


: the second step involves coating by carbohydrates on the surface of ceramic cores. There


processes generally entail the addition of polyhydroxy


promote the largely irreversible adsorption of carbohydrate on to the ceraminc surfaces. Excess and readily



desorbing carbohydrate is removed by stir cell ultra-filtration. The commonly used coating materials are

cellobiose, citrate, pyridoxal-5-phosphate, sucrose and trehalose.

Role of disaccharides11,12

Among three layers of aquasomes, carbohydrate fulfills the objective of aquasomes. As cyclodextrins which are

the complex cyclic oligosaccharides which recently have been noticed as useful pharmaceutical ingredient and

identified as � and � cyclodextrin composed of various glucose molecules forming truncated cone which can

enclose various complex structure form of proteins and peptides .The hydroxyl groups on oligomer ineract with

polar and charged groups of proteins, in a same way as with water thus preserve the aqueous structure of proteins

on dehydration. These disaccharides rich in hydroxyl group help to replace the water around polar residues in

protein, maintaining integrity in absence of water. The free bound mobility associated with a rich hydroxyl

component creates unique hydrogen binding substrate that produces a glassy aqueous state.

3. Immobilization of Drugs: The surface modified nano-crystalline cores provide the solid phase for the subsequent

nandenaturing self assembly for broad range of biochemically active molecules. The drug can be loaded by partial

adsorption.

FATE OF AQUASOMES13

The drug delivery vehical aquasome is colloidal range biodegradable nanoparticles, so that they will be more

concentrated in liver and muscles. Since the drug is adsorbed on to the surface of the system without further surface

modification they may not find any difficulty in receptor recognition on the active site so they may not find any

diffuculty in receptor recoginition on the active site so that the pharmacological or biological activity can be achieved

immediately. In normal system, the clacium phosphate is a biodegradable ceramic. Biodegradation of ceramic in vivo

is achieved essentially by monocytes and multicellular cells called osteoclasts because they intervene first at the

biomaterial implantation site during inflammatory reaction. Two types of phagocytosis were reported when cells

come incontact with biomaterial; either calcium phospahte crystals were taken up alone and then dissolved in the


cytoplasm after disappearence of the phagosomes membrane or dissol

Phagocytosis of calcium phospahte coincided with autophagy and the accumulation of residual bodies in the cell.

Fig. showing pathway for the fate of PROPERTIES OF AQUASOMES14

1. Aquasomes possess large size and active surface hence can be efficiently loaded with substantial amounts of

agents through ionic, non co-valent bonds, van der waals forces and entropic forces. As solid particles

aqueous environment, exhibit physical propertier of colloids.

2. Aquasomes mechanism of action is controlled by their surface chemistry. Aquasomes deliver contents through

combination fo specific targeting, molecular shielding, and slow and susta

3. Aquasomes water like properties provides a platform for preserving the conformational integrity and bio chemical

stability of bio-actives like proteins and peptides

4. Aquasomes due to their size and structure stability, avoid clearance

by other environmental challenges.

5. In normal system, calcium phospahte is biodegrafeable. Biodragardation in vivio achieved by monocytes and

multicellular cells called osteoclast. Two types of phagocytosis repo

dissolved in cytoplasm after disappearance of phagosome membrane or dissolution after f

heterophagosomes.13


75-1888

ter disappearence of the phagosomes membrane or dissolution after formation of heteroP


Fig. showing pathway for the fate of aquasome.

Aquasomes possess large size and active surface hence can be efficiently loaded with substantial amounts of

valent bonds, van der waals forces and entropic forces. As solid particles

aqueous environment, exhibit physical propertier of colloids.

Aquasomes mechanism of action is controlled by their surface chemistry. Aquasomes deliver contents through

combination fo specific targeting, molecular shielding, and slow and sustained release process.

Aquasomes water like properties provides a platform for preserving the conformational integrity and bio chemical

like proteins and peptides.

Aquasomes due to their size and structure stability, avoid clearance by reticuloendothelial system or degradation

In normal system, calcium phospahte is biodegrafeable. Biodragardation in vivio achieved by monocytes and

multicellular cells called osteoclast. Two types of phagocytosis reported, either crystals taken up alone and then

dissolved in cytoplasm after disappearance of phagosome membrane or dissolution after f


Page 1882

ution after formation of heteroPhagosomes.


Aquasomes possess large size and active surface hence can be efficiently loaded with substantial amounts of

valent bonds, van der waals forces and entropic forces. As solid particles dispersed in

Aquasomes mechanism of action is controlled by their surface chemistry. Aquasomes deliver contents through

ined release process.

Aquasomes water like properties provides a platform for preserving the conformational integrity and bio chemical

by reticuloendothelial system or degradation

In normal system, calcium phospahte is biodegrafeable. Biodragardation in vivio achieved by monocytes and

rted, either crystals taken up alone and then

dissolved in cytoplasm after disappearance of phagosome membrane or dissolution after formation of


CHARACTERIZATION OF AQUASOMES

1. Aquasomes are mainly characterized for structural analyses, particle size, and morphology these are evaluated by

X-ray powder diffractometry, transmission electron microscopy, and scanning electron microscopy.

2. The microphology and th size distributed were

3. The chemical composition and the crystalline structure of all sample werw obtained through X

diffractometry.

APPLICATIONS OF AQUASOMES

1. Aquasomes as red blood cell substitutes,

by heamoglobin is confomationally sensitive. By this toxicity is reduced, haemoglobin concentration of 80%

achieved and reported to deliver blood in non linear ma

2. Aquasomes have been used for successful targeted intracellular gene therapy, a five layered composition

comprised of ceramic core, polyoxyoligomeric film, therapeutic gene segment, additional carbohydarte film and a

targeting layer of conformationally conserved viral membrane protein


75-1888

CHARACTERIZATION OF AQUASOMES14

Aquasomes are mainly characterized for structural analyses, particle size, and morphology these are evaluated by

ray powder diffractometry, transmission electron microscopy, and scanning electron microscopy.

The microphology and th size distributed were obtained through images of scanning electron microscopy.

The chemical composition and the crystalline structure of all sample werw obtained through X

Aquasomes as red blood cell substitutes, haemoglobin immoblized on oligomer surface because release of oxygen


achieved and reported to deliver blood in non linear manner like natural blood cells15.

Aquasomes have been used for successful targeted intracellular gene therapy, a five layered composition

of ceramic core, polyoxyoligomeric film, therapeutic gene segment, additional carbohydarte film and a

served viral membrane protein15.


Page 1883

Aquasomes are mainly characterized for structural analyses, particle size, and morphology these are evaluated by

ray powder diffractometry, transmission electron microscopy, and scanning electron microscopy.

obtained through images of scanning electron microscopy.

The chemical composition and the crystalline structure of all sample werw obtained through X-ray powder

haemoglobin immoblized on oligomer surface because release of oxygen


Aquasomes have been used for successful targeted intracellular gene therapy, a five layered composition

of ceramic core, polyoxyoligomeric film, therapeutic gene segment, additional carbohydarte film and a



Fig showing: Enhanced gene delivery with ultrasound and microbubbles. Presence of gas in gene-filled

microbubble allows ultrasound energy to “pop” the bubble. An energetic wave is then created that allows genetic

material to enter surrounding cells thus an another emerging technique which can be called upon as gasosomes.

3. Aquasomes used as vaccines for delivery of viral antigen i.e. Epstein-Barr and Immune deficiency virus to evoke

correct antibody, objective of vaccine therapy must be triggered by cnformationally specific target molecules16.

4. Aquasomes for pharmaceuticals delivery i.e insulin, developed because drug acitivity increased to 60% as

compared to i.v. administration and toxicity not reported17.

5. Aquasomes also used for delivery of enzymes like DNAase and pigment/dyes because enzymes activity fluctuates

with molecular conformation and cosmetic properties of pigments are sensitive to molecular conformation.

6. Various Recomninant Products used for the delivery through aquasomes thus preventing degradation in stomach

pH and increases the drug targeting and availability.

FDA APPROVED (RECOMBINANT GENES) PROTEINS WHICH CAN BE TRANSFERRED THROUGH AQUASOMES18.

TRADE NAME RECOMBINANT PRODUCT YEAR OF APPROVAL Activase Tissue plasminogen activator 1987 US Epogen/procrit Erythropoietin (epoetin�� 1989/1990 US Recombinate Clotting factor VIII 1992 US Kogenate; Helixate Clotting factor VIII 1993 US Kogenate FS; Clotting factor VIII 1993 US Helixate FS (sucrose formulation) 2000 US Cerezyme � –glucocerebrosidase 1994 US Avonex IFN-�-1a 1996 US Benefix Clotting factor IX 1997 US Rituxan (US)/ Mabthera(EU) Anti-CD20 chimeric mAb 1997 US Gonal-f Follicle stimulating hormone 1997 US

(follitropin �� 1995 EU

Simulect Anti-IL2 receptor- � chimeric mAb 1998 US Remicade Anti- TNF � chimeric mAb 1998 US Herceptin Anti-HER 2 humanized mAb 1998 US Enbrel TNF � receptor- IgG fusion protein 1998 US Thyrogen Thyrotropin � 1998 US Novoseven Clotting factor VII a 1999 US Ovidrel or Ovitrelle Human chorionic gonadotropin � 2000 US Refacto B domain-delected clotting factor VIII 2000 US


DIFFERENCE BETWEEN AQUASOMES AND LIPOSOMES

Liposomes 1. Liposomes are Concentric bilayered

enclosing aqueous volume which by membranous phospholipids bilayer

2. Liposomes involves entrapment of aqueous

TNKase Tissue plasminogen activatorAranesp Darbepoetin Xigris Activated

(Antithrombotic)

Osigraft (Osteo-genic protein 1) Osteogenic proteinmorphogenetic protein

Refib IFNHumira AntiAmevive LFAFabrazyme -galactosidase AAldurazyme Laronidase (Xolair AntiAdvate Clotting factor VIII (plasma/albumin

free)Raptiva AntiAvastin AntiLuveris Luteinizing hormoneNaglazyme N-acetylgalactosamineOrencia Ig-CTLA4 fusion (antirheumatic)Myozyme Acid Vectibix AntiSoliris Anti

humanized mAbMircera Methoxy polyethylene glycolRebif New formulation rh IFNOptaflu CellRecothrom Topical human thrombinXyntha B domain


75-1888

DIFFERENCE BETWEEN AQUASOMES AND LIPOSOMES

Aquasomes Concentric bilayered vesicles

enclosing aqueous volume which is enclosed by membranous phospholipids bilayer.

1. Aquasomes are nanoparticle composed of nanocrystalline core particle surrounded by oligomeric layer to which drug is adsorbed forming complex.

Liposomes involves entrapment of aqueous 2. Since aquasomes involve strong linkage

Tissue plasminogen activator 2000 US Darbepoetin 2001US Activated protein C 2001 US

(Antithrombotic) 2002 EU

Osteogenic protein-1: bone morphogenetic protein-7

2001 US

IFN- -1 2002 US Anti-TNF human mAb 2002 US LFA-3-IgG fragment fusion protein 2003 US

galactosidase A 2003 US Laronidase ( -L-iduronidase) 2003 US Anti-IgE humanized mAb 2003 US Clotting factor VIII (plasma/albumin free)

2003 US

Anti-CD11a humanized mAb 2003 US Anti-VEGF humanized mAb 2004 US Luteinizing hormone 2004 US

acetylgalactosamine-4-sulfatase 2006 EU CTLA4 fusion (antirheumatic) 2005 US

Acid -glucosidase 2005 US Anti-EGFR human mAb 2006 US Anti-C5 (Complement protein) humanized mAb

2007 US

Methoxy polyethylene glycol-epoetin 2007 US rh IFN- -1a 2007 EU Cell-based seasonal influenza vaccine 2007 EU Topical human thrombin 2008 US B domain-deleted clotting factor VIII 2008 US


Page 1885

Aquasomes are nanoparticle composed of nanocrystalline core particle surrounded by oligomeric layer to which drug is adsorbed

Since aquasomes involve strong linkage



drug substance with the help of phospholipids between drug, core and oligomeric layer so lead to the formation of stable molecular structure thus inhances bioavailablity and targeting

3. Fast degradation in the body as no complex formation takes place between the drug and phospholipids.

3. Slow degradation in the body as it involves formation of stronger complex thus increases boiavailablity of protiens and peptides.

4. Entrapment technique is employed is hold the drug

4. Adsorption technique is employed for complexation with biochemically active drugs

Conclusion:

Aquasomes are the promising nanobiopharmaceutical novel drug carrier system based on the fundamental principle

of self assembly. The drug candidates which are delivered through aquasomes are peptide and protein hormones,

antigens and genes and show better biological activity even in case of conformationally sensitive ones. This

conformational stability is mainly provided by the unique carbohydrates that prevents the destructive drug-carrier

interaction and thus preserve spatail qualities & crystalline core gives structural stability and integrity. Various other

range of broad molecules delivered through aquasomes include viral antigens, heamoglobin and insulin. This strategy

may be beneficially extended to the novel delivery of other bioactive molecules.

Refrences:

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2. Crowe, J.H.; Crowe, L.M.; Carpenter, J.F.; Rudolph, A.S.; Wistrom, C.A.; Spargo, B.J. and Acnhordoguy.T.J”

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16. Kossovsky, N.; Gelman, A; Sponsler, E.; Rajguro, S.; Tones, M; Mena, E.; Ly, K and Festeljian, A”Preservation

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18. http://en.wikipedia.org/wiki/List_of_recombinant_proteins

Corresponding Author:

Rathore Priyanka*,*,*,*,

Email: [email protected]

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