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CONTENTS 2 Introduction Structure Why Erythrocytes as carriers Basic Features Of Erythrocytes Source and isolation Of Erythrocytes Method Of Drug Loading Characterization parameters Advantages of Resealed Erythrocytes Disadvantages of Resealed Erythrocytes Applications References

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3 erythro = red and cytes = cell erythrocyte is red cell. Erythrocyte is biconcave discs , anucleate filled with hemoglobin (Hb), a protein that functions in gas transport. Healthy adult male=4.5millions/µml Healthy adult female=4.8million/µml Erythrocytes have a life of around 120 days, whereupon they degenerate. They follow a established life cycle . INTRODUCTION

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4 Erythrocytes (RBCs) contain oxygen carrying protein hemoglobin, which is a pigment that gives whole blood its red color . Because matured RBCs have no nucleus, all their internal space is available for oxygen transport.


WHY ERYTHROCYTES AS CARRIERS 5 The desirable properties, which substantiate the suitability of red blood cells (erythrocytes) as drug carriers are :- Biodegradability Circulate throughout the circulating system large quantities of material can be encapsulated with small volume of cells. Can be utilized for organ targeting within RES. Erythrocytes are biocompatible .


BASIC FEATURES OF ERYTHROCYTES 6 They are non-nucleated Do not synthesize new carbohydrates, proteins and lipids and replace them with plasma components to rebuild its membrane constituents It have a solid content of about 35% most of which is haemoglobin which remains tightly bound to the stroma of the cell membrane. The osmotic pressure of the interior of the erythrocytes is equal to that of plasma and termed as isotonic. Red blood cells show flexibility.

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7 Biodegradability & biocompatibility. Circulate throughout the circulatory system. Inert environment. Prevention of undesired immune response. Can be utilized for organ targeting within RES. A longer life span as compared to synthetic carriers. Decrease in side effect of drugs. Increase in drug dosing interval. Easy control during life span ranging from minutes to months. Large qty. of material can be encapsulated within small volume of cells. Advantages

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8 Disadvantages They are removed in vivo by RES so may cause toxicological problems. Rapid leakage of certain encapsulated from the loaded erythrocytes. Several molecules may alter the physiology of the erythrocyte. Lesser standardization in their preparation, compared to other carrier systems. The storage of the loaded erythrocytes is a further problem involving carrier erythrocytes Liable to biological contamination due to the origin of the blood, the equipment and the environment

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ISOLATION OF ERETHROCYTES Blood is collected into heparinized tubes by venipuncture The whole blood is centrifuged at 2500 rpm for 5 min at 4 ±1 0 C in a refrigerated centrifuge packed cells washed three times with phosphate buffer saline (pH=7.4). The washed erythrocytes are diluted with PBS and stored at 4 o C until used. 9

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1. Hypotonic Haemolysis and Isotonic Resealing Methods This method is based upon hypotonic lysis of cells in solution containing the drug/enzyme to be entrapped followed by restoration of tonicity to reseal them. These ruptured membranes can be resealed by raising the salt concentration to its original (isotonic) levels and upon incubation, The resealed erythrocytes resume their normal biconcave shape and recover their normal impermeability to both macromolecules and ions. 11

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( i ) Dilutional Haemolysis Population of erythrocytes when exposed to hypotonic saline solution (0.4% NaCl ), swells until it reaches a critical value of volume or pressure where membrane ruptures and becomes permeable to macromolecules and ions, therefore permitting the escape of cellular components . 12

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(ii) Preswell Dilutional Haemolysis The technique is based upon initial controlled swelling of erythrocytes without lysis by placing them in slightly hypotonic solution followed by centrifugation at low 'g' to take them up to point of lysis . Finally, the addition of small volume of drug solution to attain drug loaded resealed erythrocytes. 13

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(iii) Isotonic Osmotic Lysis Haemolysis in isotonic solutions can be achieved both by chemical and physical means. If erythrocytes are incubated in solutions of a substance with high transerythrocytic membrane permeability (i.e., small reflection coefficient as defined by the thermodynamics of irreversible processes) the solute will diffuse into the cells due to inwardly directed chemical potential gradient. This will be followed by water uptake until osmotic equilibrium is restored. 14

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(iv)Dialysis: Loading of erythrocytes are reported but all take advantage of the common principle that the semi permeable dialysis membrane maximizes the intracellular: extracellular -volume ratio for macromolecules during lysis and resealing, but also allows for free flow of small ions, responsible for lysis and resealing of the erythrocytes. 15

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2 . Loading by Chemical Perturbation of Membrane This method is based upon the observation that the permeability of the erythrocytic membrane is increased, when it is exposed to some chemical agents. Amphotericin B, a polyene antifungal antibiotic, damages microorganism by increasing permeability of their membranes to metabolites and ions. 16

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Lipid vesicles containing drug can be directly fused with human erythrocytes leading to exchange of lipid entrapped drug 3.Loading by Lipid Fusion 17



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In vitro characterization 19


IN VIVO SURVIVAL AND IMMUNOLOGICAL CONSEQUENCES A rapid loss of cells during first 24 hrs followed by much slower loss afterwards. The first phase represents the cells that are severally damaged during the drug loading procedures. Resealed erythrocytes prepared from RBCs of chicken, rats and rabbits exhibited relatively poor circulation profile as compared against unloaded normal erythrocytes. 20


APPLICATION OF RESEALED ERYTHROCYTES Erythrocytes as drug/ enzyme carriers: Erythrocytes as carriers for enzymes. Erythrocytes as carriers for drugs. Erythrocytes as carriers for proteins and macromolecules. Drug targeting: Drug targeting to RES organs Surface modification with antibodies Surface modification with Glutaraldehyde Surface modification involving sulphydryls 21

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Drug targeting to Liver Enzyme deficiency/replacement therapy Treatment of liver tumors Treatment of parasitic diseases Removal of RES Iron Overload Targeting to sites other than RES- rich organs Magnet-responsive Erythrocyte Ghosts Photosensitized Erythrocytes Ultrasound mediated Delivery of Erythrocytes loaded drugs Antibody Anchored Erythrocytes (Immunoerythrocytes). Erythrocytes as Circulating Bioreactors Delivery of Antiviral Agents. 22


RECENT DEVELOPEMENTS NOVEL SYSTEMS Nanoerythrosomes An erythrocyte based new drug carrier, named nanoerythrosome has been developed which is prepared by extrusion of erythrocyte ghosts to produce small vesicles having an average diameter of 100 nm. Erythrosomes Erythrosomes are specifically engineered vesicular systems in which chemically cross-linked human erythrocyte cytoskeletons are used as a support upon a lipid bilayer is coated. 23


ADVANTAGES OF RESEALED ERYTHROCYES Their biocompatibility, Their biodegradability with no generation of toxic products The considerably uniform size and shape of the carrier Prevention of degradation of the loaded drug from inactivation By endogenous chemicals The wide variety of chemicals that can be entrapped The modification of pharmacokinetic and pharmacodynamic Parameters of drug The prevention of any undesired immune response against the loaded drug 24


DISADVANTAGES Disadvantages include a need for a Dose dumping may be there They have limited potential as carrier to non phagocytic target tissue Time consuming process 25

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Marketed products currently under study: Antiviral drug i.e. AZEDOTHYMIDINE. Antimycobacterial drug i.e. ETHAMBUTOL. AZTpEMB , AZTpEMBpAZT , AZTp2EMB are some of the compounds, synthesized which contain anti-retroviaral and antimicrobial activity are used in the treatment of M.AVIUM infection and in bacterial infections of AIDS. Marketed products 26


REFERENCES Controlled and Novel Drug Delivery, edited by N.K Jain, CBS Publishers, pp.256-281. Targeted & Controlled Drug Delivery Novel Carrier Systems, by S.P Vyas and R.K Khar, CBS Publishers, pp.387-413. 27 27

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