RESEALED ERYTHROCYTES - AS A CARRIER

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ABOUT AUTHORS:
Meenu Sharma*, Saroj  jain
Department of Pharmaceutics, Hindu college of pharmacy
Panchayat Bhawan, Gohana Road, Sonipat (Haryana)
meenu99sharma@gmail.com

ABSTRACT
Amongst various carriers explored for target oriented drug delivery, vesicular, microparticulate and cellular carriers meet several criteria rendering them useful in clinical applications. Lymphocytes, leukocytes, platelets, granulocytes and erythrocytes have been  proposed as a cellular carriers.  Erythrocytes, also known as red blood cells, and have been the most extensively investigated and found to possess great potential in novel drug delivery. The biocompatibility, non- pathogenicity, non-immunogenicity and biodegradability make them unique and useful carriers. The prime function of these RBCs is to transport gases for respiratory processes. Carrier erythrocytes are prepared by collecting blood sample from the organism of interest and separating erythrocytes from plasma. By using various methods the cells are broken and the drug is entrapped into the erythrocytes, finally they are resealed and the resultant carriers are then called "resealed erythrocytes". Erythrocytes have been proposed as a carriers for a wide range of bioactive components including drugs enzymes, pesticides, DNA molecules and others.

REFERENCE ID: PHARMATUTOR-ART-2149

PharmaTutor (ISSN: 2347 - 7881)

Volume 2, Issue 5

Received On: 03/03/2014; Accepted On: 09/03/2014; Published On: 01/05/2014

How to cite this article: M Sharma, S Jain; Resealed Erythrocytes - As a Carrier; PharmaTutor; 2014; 2(5); 10-18

INTRODUCTION
Current research is aimed at development of drug delivery system (DDS)with maximum therapeutic benefits.

Concepts are based on controlled drug delivery i.e Biotechnology, Polymer sciences and pharmaceuticals sciences. To achieve a required therapeutic concentration of  drug which has to be administered in large quantities are used, the major part of which is just wasted in normal tissues. Ideally, a perfect drug should exert it Pharmacological activity only at the target site, using the lowest concentration possible and without negative effects on non-target compartments. Target specificity would also reduce the dosage and frequency of administration. The delivery systems currently available enlist carriers that are either simple, soluble macromolecules (such as monoclonal antibodies, soluble synthetic polymers, polysaccharides and particulate biodegradable polymers) or more complex multi-component structures (microcapsules, Micro particles, cells, cell ghosts, lipoproteins, liposome’s, erythrocytes). Erythrocytes, the most abundant cells in  human body, have potential carrier capabilities for delivery of drugs. Erythrocytes are biocompatible, biodegradable, possess very long circulation half lives and can be loaded with a variety of chemically and biologically active compounds using various chemical and physical methods(1) Erythrocyte is the red blood cells, biconcave discs, enucleate filled with hemoglobin (Hb), a protein that functions in gas transport  contain  plasma protein spectrin, in healthy adult male=4. 5millions/μ ml and in healthy adult female=4. 8million/μ -ml. Immature RBC are called Reticulocytes.(2)

Erythrocytes:
Erythrocytes are natural products of  body, biodegradable in nature, Isolation of these are easy and large amount of drug can be loaded in small volume of cells, non-immunogenic in action and can be targeted to disease tissue or organ, prolong the systemic activity of  drug while residing for a longer time in the body, protect  premature degradation, inactivation and excretion, of proteins and enzymes, act as a carrier for number of drugs, target the drugs within the reticulo-endothelial system (RES) as well as non RES organs/sites. They have the capacity to carry large amounts of drug; and can behave as a slow-release long acting systems. Potential clinical indications for “RES targeting” include iron over storage diseases, parasitic diseases, hepatic tumors, cancer and lysosomal storage diseases  carriers (3).

Figure no: 1 Erythrocytes

Erythrocytes can be used as carriers in two ways(4):
1. Targeting particular tissue/organ.
For targeting, only the erythrocyte membrane is used. This is obtained by splitting the cells in hypotonic solution and after introducing the drug into the cells, allowing them to reseal into spheres. Such erythrocytes are called Red cell ghosts.

2. For continuous or prolonged release of drugs-
Alternatively, erythrocytes can be used as a continuous or prolonged release system, which provide prolonged drug action. There are different methods for encapsulation of  drugs within erythrocytes. They remain in the circulation for prolonged periods of time (up to 120 days) and release the entrapped drug at a slow and steady rate.

Resealed Erythrocytes
For drug-loading carrier erythrocytes are prepared simply by collecting blood samples from the organism of interest, separating erythrocytes from plasma, entrapping drug in the erythrocytes, and resealing the resultant cellular carriers (5). Hence, these carriers are called resealed erythrocytes. The overall process is based on  response of these cells under osmotic conditions (6)

Advantages of resealed erythrocytes as drug carriers:
Resealed erythrocytes  have the following advantages:(7,8,9,10,11)
· biodegradability with no generation of toxic products.
· considerably uniform size and shape.
· Prevention of degradation of loaded drug from inactivation by endogenous chemicals.
· wide variety of chemicals can be entrapped.
· The modification of pharmacokinetic and pharmacodynamic parameters of drug.
· Attainment of steady-state plasma concentration which decreases fluctuations in concentration.
· Protection of organism against toxic effects of drugs (e.g. anti-neoplastics).
· have ability to circulate throughout the body facilities for separation technique, handling, transfusion, and working with erythrocytes are available.
· Prevention of any undesired immune response against the loaded drug.
· ability to target the organs of non RES.

ISOLATION OF ERYTHROCYTES:

  • Blood is collected into heparin- zed  tubes by vein-puncture.
  • Blood is withdrawn from cardiac/splenic puncture (in small animal) and through veins (in large animals)  in a syringe containing a drop of anti-coagulant.
  • The whole blood is centrifuged at 2500 rpm for 5 min. at 4 ±10°C in a refrigerated centrifuge.
  • The serum and Buffy coats are carefully removed and packed cells washed three times with phosphate buffer saline (pH=7.4).
  • The washed erythrocytes are diluted with PBS and stored at 40°C for as long as 48 h before use.
  • Various types of mammalian erythrocytes have been used for drug delivery, including erythrocytes of  mice, cattle, pigs, dogs, sheep, goats, monkeys, chicken, rats, and rabbits(12,13)

Methods of drug loading(14):
Several methods can be used to load drugs or other bioactive compounds in erythrocytes including physical (e.g., electrical pulse method) osmosis-based systems, and chemical methods (e.g., chemical perturbation of  erythrocyte  membrane)

1. Hypotonic hemolysis (15) :
This method is based on the ability of erythrocytes to undergo reversible swelling in a hypotonic solution. Erythrocytes have an exceptional capability for reversible shape changes with or without accompanying volume change and for reversible deformation under stress. An increase in volume leads to an initial change in  shape from biconcave to spherical. This change is attributable to the absence of superfluous membrane; hence the surface area of  cell is fixed. The cells assume a spherical shape to accommodate additional volume while keeping the surface area constant. The volume gain is ~25–50%. The cells can maintain their integrity up to a tonicity 150 m osm/kg, above which the membrane ruptures, releasing the cellular contents. At this point (just before cell lysis), some transient pores of 200–500 Å are generated on the membrane. After cell lysis, cellular contents are depleted. The remnant is called an erythrocyte ghost.

Figure 2: Hypotonic hemolysis

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