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R. P. Patel et al. / Journal of Pharmacy Research 2009, 2(6),1008-1012 Available online through www.jpronline.info
An Overview of Resealed Erythrocyte Drug Delivery
*R. P. Patel, M. J. Patel, and N. A. Patel *Department of Pharmaceutics, S.K. Patel College of Pharmaceutical Education and Research, Ganpat University, Ganpat vidyanagar, Kherva, Mehsana-Gozaria Highway, PIN-390 001, Gujarat, India. Received on: 22-01-2009; Accepted on: 19-03-2009 ABSTRACT Among the various carriers used for drug delivery, erythrocytes (red blood cells, RBC) constitute potential biocompatible carriers since they possess several properties which make them unique and useful carriers. Erythrocytes are biocompatible, biodegradable, possess long circulation half lives, and can be loaded with a variety of biologically active compounds using various chemical and physical methods. This systemic review deals with advantages, requirement, methods of drug loading, characterizations, and application of erythrocyte mediated drug delivery. Keywords: Erythrocyte mediated drug delivery, Carriers, Drug loading. 1. INTRODUCTION Current research is aim at development of drug delivery system with maximum therapeutic benefits for safe and effective management of disease(s). The development of drug delivery system in future will be aimed to maximize therapeutic performance, eliminate undesirable side effect of drug and increase patient compliance. The idea of a drugcarrier system with target specificity has fascinated scientists and tremendous efforts have been made to achieve this goal.1 Erythrocytes, also known as red blood cell (RBCs), have been extensively studied for their potential carrier capabilities for the delivery of drugs and drug-loaded microspheres.2-4 Such drug-loaded carrier erythrocytes are prepared simply by collecting blood samples from the organisms of interest, separating erythrocytes from plasma, entrapping drug in the erythrocyte and resealing the resultant cellular carriers 1. Hence these carriers are called as resealed erythrocytes. The overall process is based on the response of these cells under osmotic condition. Upon reinjection, the drug-loaded erythrocytes serve as slow circulating depots and target the drug to a reticuloendothelial system (RES).5 2. Anatomy, physiology and composition of RBCs 6 RBCs have shapes like biconcave discs with a diameter of 7.8 µm and thickness near 2.2 µm. Mature RBCs have a simple structure. It is also in elastic in nature. Their plasma membrane is both strong and flexible, which allows them to deform without rupturing as they squeeze through narrow capillaries. RBCs lack a nucleus and other organelles and can neither reproduce nor carry on extensive metabolic activities. RBCs are highly specialized for their oxygen transport function, because their mature RBCs have no nucleus, all their internal space is available for oxygen transport. Even the shape of RBC facilities it’s function. A biconcave disc has a much greater surface area for the diffusion of gas molecules in to and out of the RBC than would; say
*Corresponding author. Dr. Rakesh P. Patel Asst. Professor and Head of Pharmaceutics & Pharmaceutical Technology Department Phone/Fax: 02762-286082, 02762-286080 Mobile: +91-9879106580 E-mail: firstname.lastname@example.org
a sphere or a cube. The red blood cell membrane, a dynamic, semipermeable components of the cell, associated with energy metabolism in the maintenance of the permeability characteristic of the cell of various cations (Na -, K+ ) and anions (Cl-, HCO3- ). Each RBC contains about 280 million hemoglobin molecules. A hemoglobin molecules consists of a protein called globin, composed of four polypeptide chains; a ring like non-protein pigment called a heme, is bound to each of the four chains. At the center of the heme ring combine reversibly with one oxygen molecule, allowing each hemoglobin molecule to bind four oxygen molecules. RBCs include water (63%), lipids (0.5), glucose (0.8%), mineral (0.7%), non-hemoglobin protein (0.9%), methehemoglobin (0.5%), and hemoglobin (33.67%). 3. Advantages: 7-16 • Biocompatible, particularly when autologous cells are used hence no possibility of triggered immune response. • Natural product of the body, which are biodegradable in nature. • Biodegradability with no generation of toxic products. • Considerable uniform size and shape of carrier. • Relatively inert intracellular environment can be encapsulated in a small volume of cells. • Isolation is easy and large amount of drug can be loaded. • Prevention of degradation of the loaded drug from inactivation by endogenous chemical. • Entrapment of wide variety of chemicals can be possible. • Entrapment of drug can be possible without chemical modification of the substance to be entrapped. • Possible to maintain steady-state plasma concentration, decrease fluctuation in concentration. • Protection of the organism against toxic effect of drug. • Targeting to the organ of the RES. • Ideal zero-order drug release kinetic. • Prolong the systemic activity of drug by residing for a longer time in the body. • Carrier for number of drugs. • A longer life span in circulation as compared to other synthetic carrier
Journal of Pharmacy Research Vol.2.Issue 6.June 2009
hematological analyzer Stepwise incubation with isotonic to hypotonic saline solutions and determination of drug and hemoglobin assay Dilution with distilled water and estimation of drug and hemoglobin Passage of cell suspension through 30-gauge hypodermic needle at 10 ml/min flow rate and estimation of residual drug and hemoglobin. Patel et al. Once the membrane is perforated. Optical microscopy Diffusion cell. the intracellular and extracellular solutes of erythrocytes are exchanged by osmotic lysis and resealing. Isotonic osmotic lysis23 Resealed erythrocytes were prepared under isotonic conditions. Generally. 5. The resulting erythrocytes contain vacuoles and probably have different in vivo survival characteristics from resealed cells.R. — Impermeable only to large molecules. energy metabolism. dialysis Deproteination of cell membrane followed by assay of resealed drug. Non-polar molecules may be entrapped in erythrocyte in their respective salts. 5. 5.).000 Daltons in size) can be entrapped in erythrocyte. The swollen ghosts so prepared exhibit larger (>0. enzyme and small molecules.25 . process is time • • • Easy control during life span ranging from minutes to months. 2(6). The electromechanical compression of the membrane after breakdown leads to formation of pores. Methods of drug loading Several methods can be used to load drugs or bioactive compounds in erythrocyte. the method is based on the observation that electrical shock brings about irreversible changes in an erythrocyte membrane.3 Entrapment by Endocytosis The vesicle membrane separates the endocytosed substance from the cytoplasm.1008-1012 Table 1: Different types of methods for drug loading in erythrocyte Method Dilution method22 Procedure Based upon hypotonic lysis of cells in a solution containing the drug/enzyme to be entrapped followed by restoration of tonicity to reseal them and also ability of erythrocytes to undergo reversible swelling in a hypotonic solution. consuming. The drug present will be encapsulated within the erythrocytes membrane by this process21 . Better in vivo survival. which may shelter drugs prone to inactivation in erythrocytes or alternatively protect the erythrocytes from drug. Characterizations23.23 6. mostly at the advancing lip of the stoma. Time consuming. Finally.2. Vigorous shaking followed by hemoglobin estimation ESR method Erythromycin sedimentation rate III Biological characterization Sterility Sterility test Pyrogenicity Rabbit method.Issue 6. Also known as electroporation. 5. 30-45% Good retention of — cytoplasm constituents and good survival in vivo. Different types of this methods summarized in table 1. LAL test Animal toxicity Toxicity tests IV Miscellaneous Cell size. regardless of the size of the pores. Haemolysis in isotonic solutions can be achieved both by chemical agent and physical methods. / Journal of Pharmacy Research 2009. This method is efficient for loading large particles such as virus (up to 100 nm dia. the molecules should be polar.2 Electro-insertion or Electro-encapsulation Electrical pulse method is used to encapsulate bioactive molecules. rheological properties etc.26 5. Several classes of drugs as reported by Schrier. Molecules which interact with the membrane and cause deleterious effects on membrane structure are not considered to be appropriate for encapsulation in erythrocyte17-20. when it is exposed to some chemical agents. pulse duration and ionic strength of the suspending medium. The use of transient electrolysis is to generate desirable membrane permeability for drug loading into red blood cells. Scanning electron microscopy. Disadvantages Entrapment capacity low. Requirements for encapsulation A wide variety of biologically active substance (5000-600. non-polar and hydrophobic molecules have also been successfully.27 Table 2: Summary of characterization parameters & their determination for resealed RBCs Parameter I Physical characterization Shape and surface morphology Vesicle size and size distribution Drug release Drug content Surface electrical potential Surface pH Deformability II Cellular characterization % Hb content Cell volume % cell recovery Osmotic fragility Osmotic shock Turbulent shock Method / instrument used Transmission electron microscopy.4 Loading by Chemical Perturbation of Membrane (Drug Mediated Loading) This method is based upon the observation that the permeability of the erythrocytic membrane is increased. prepared using other methods. density gradient separation — Journal of Pharmacy Research Vol. 23 Dialysis It can be carrying out lysis and resealing within a dialysis tube using hypotonic and isotonic solution. The drug substances are trapped in these endocytic vacuoles. 1987 can produce this phenomenon of visible investigation. % Loading 1-8% Advantages Fastest and simplest. membrane fluidity. Phase contrast microscopy. The potential difference across the membrane is built up either directly by inter.June 2009 1009 . P. This allows the low molecular weight substances to get entrapped. A decrease side effect of drugs.and intracellular electrodes or indirectly by applying internal electric field to the cells. mean cell volume. A considerable increase in drug dosing interval with drug residing in therapeutic window region for longer time periods. Sucrose is routinely used as a marker for encapsulation studies. The extent of pore formation depends upon the electric field strength. rediolebelling Zeta potential measurement pH sensitive probes Capillary method Deproteinization of cell membrane followed by hemoglobin assay Laser light scattering Neubaur’s chamber.1 Osmotic method In this process. hydrophilic. Preswell dilution23 The technique is based upon initial controlled swelling of 20-70% erythrocytes without lysis by placing them in slightly hypotonic solution followed by centrifugation at low ‘g’ to take them up to point of lysis. The components can be entrapped when an electric pulse of greater than a threshold voltage of 1-10 kV/cm is applied for 20160 microsec in media and resealed in osmotic medium. inside-out endocytic vacuole formation. lipid composition. Better in vivo surveillance. Optical microscopy Transmission electron microscopy.5 µ diameter) endocytic vacuoles. however the membrane still remain impermeable to its cytoplasmic macromolecules 24. especially for low molecular weight drug. Drug induced endocytosis is quite common and a variety of amphiphilic cations/drugs produce first stomatocytosis and then. include physical osmotic based systems and chemical methods. ions rapidly distribute between the extra-and intracellular space to attain Donnan equilibrium. the addition of small volume of drug solution to attain drug loaded resealed erythrocytes. 4.
when antibody molecules are introduced using erythrocytic carrier system. Resealed erythrocytes. can therefore be used to target the liver and spleen. A combination of chemotherapy and photodynamic therapy 38 could be a useful modality in the treatment of tumors of body located at site other than RES predominant organs. Localization to a particular location under the influence 36. Antibody Anchored Erythrocytes (Immunoerythrocytes): Ultrasound Mediated Delivery of Erythrocytes loaded drug(s): Antibody coating of resealed drug carrier erythrocytes colloidal particles and red blood cells Objective/Purpose Ref. blood pressure and renal functions. macrophage-contained leishmania. A protein or nucleic acid was injected into eukaryotic cells by fusion process. P. The rate of diffusion depends upon the rate at which a particular molecule penetrates through a lipid bilayer it is greatest for molecule with high lipid solubility and gradually goes down with polarity or charged groups of the molecule. / Journal of Pharmacy Research 2009. Prolongation of release could presumably be accomplished by entrapment of potent inhibitors of the appropriate transport protein along with the drug. b) In – Vivo Applications i) Targeting of bioactive agents to RE System Damaged erythrocytes are rapidly cleared from circulation by phagocytic Kupffer cells in liver and spleen. phagocytosis. Table 4: Resealed erythrocytes used in other than RES organ targeting Approaches Type of drugs Magnet-responsive Erythrocyte Ghosts encapsulation of small paramagnetic particles into erythrocytes Photosensitized Erythrocytes Methotrexate and photosensitized by subsequent exposure to a haematoporphyrin derivative.g. etc encapsulated in erythrocytes Pentamidine loaded. The biochemical defects such as the glucose-6-phosphate dehydrogenase (G6PD) deficiency can be useful tool for discerning the mechanism that eventually causes these effects. Patel et al. Carboplatin.e. carbohydrates such as sialic acid and sulphydryl. 39 Delivery to tissue through micro vessel ruptures created by targeted micro bubble destruction with ultrasound. and use of specific transport system. Drug release characteristics of loaded drugs There are mainly three ways for a drug to efflux out from erythrocyte carrier’s i. The most frequent in vitro application of RBC is that of micro-injection.Issue 6.28 They found that gluteraldehyde fixation of erythrocytes renders them resistant to both osmotic shock and turbulence induced lysis. To promote excretion of iron in patients with excess body stores. 37 of external magnetic field. The various approaches to modify the surface characteristics of erythrocytes include surface modification with antibodies. Gentamycin. Talwar & Jain was selectively targeted drug loaded erythrocytes after gluteraldehyde treatment to the liver or spleen.June 2009 1010 . by modifying their membranes. they immediately diffuse throughout the cytoplasm. diffusion through the membrane of the cell. 8. metronidazole. Loaded cells survived for 10 days in treated patient and no untoward reactions were found with respect to blood counts.R. OR As a phototriggered carrier/delivery system for methotrexate in tumor therapy.1008-1012 Table 3: Resealed erythrocytes used in RES targeting Name of Drug(s) Treatment/Diseases Treatment of lysosomal storage diseases Lysosomal enzymes. Resealed erythrocytes could be safely infused into patients and the loading at a high haematocrit value resulted into a long circulation time in-vivo. Applications of Resealed Erythrocytes Resealed erythrocytes have been proposed for a variety of applications in human and veterinary medicine. an iron-chelating drug in erythrocyte ghosts Murine carrier erythrocytes containing bovine rhodanese and sodium thiosulphate Purpose To deliver lysosomal enzymes and drugs to lysosomes of the erythrophagocytic cells. Adriamycin. at low concentration glutaraldehyde treated cells are removed by spleen whereas at high concentration treated cells are removed by the liver. 2(6). considerable control over the rate of drug release is possible by introducing or eliminating polor or charged subsistent. Various applications can be summarized as under: a) In-Vitro Applications 29 Carrier RBCs have proved to be useful for a variety of in vitro tests.2. Antibody RBC auto-injected into living cells has been used to confirm the site of action of fragment of diphtheria toxin. e. Other in vitro tests include utilization of erythrocytes carrier to introduce ribosome inactivating proteins into cells by fusion technique. Similarly. immunoglobulin-G coated erythrocytes Glutaraldehyde treated erythrocytes Removal of RES iron overload Removal of Toxic Agents Desferoxamine. Targeting of drugs in the treatment of parasitic diseases in which the parasite resides in the organs of RES. gluteraldehyde. Antibodies introduced using RBC mediated microinjection is recorded not to enter the nucleus. Many substances enter cells by a specific membrane protein system because the carriers are proteins with many properties analogous to that of enzymes including both purine and pyrimidine nucleoside is transported extremely rapidly by facilitated diffusion. ii) Targeting to sites other than RES-rich Organs Resealed erythrocytes have the ability to deliver a drug or enzyme to the macrophage-rich organs. Drug targeting to the RES. Liver targeting of an antimalarial agent . Enzymes content within carrier RBC could be visualized with the help of cytochemical technique. Obviously. Toxicological. 13-galactosidase and 6-giucosidase Glucocerebrosidase Treatment of Gaucher’s disease Treatment of liver tumors Treatment of parasitic diseases Anticancer like Bleomycin.primaquine phosphate and an antiamoebic agent. The immunological characteristics of a drug carrier are of two types: the immunogenicity of the carrier itself and the ability of the carrier to protect an entrapped drug from immunological detection. Reference 30 31 32 33 28 34 35 7. 9. Targeting to hepatic carcinomas. Some of the representative approaches are discussed in brief. For in vitro phagocytosis cells have been used to facilitate the uptake of enzymes by phagolysosomes. C-glucuronidase. thus limiting the studies to the cytoplasmic level. It is concluded that. Antagonism of cyanide intoxication ORTo antagonize the lethal effects of potassium cyanide in mice. 40 Journal of Pharmacy Research Vol. Immunological and Targeting Potential The use of erythrocytes circulating blood carrier have shown no toxic effect as evident from animal studies. Organ targeting other than RES have been tried recently with resealed erythrocytes.
Red Blood Cells for Drug Delivery. Resealed erythrocytes serve as an ideal carrier for antineoplastic agents. B. iv) Erythrocytes as Carriers for Drugs 29 Various bioactive agents encapsulated in erythrocytes are developed for the slow and sustained release in circulation to allow effective treatment of parasitic diseases.E. The Cardiovascular System The Blood in Principles of Anatomy and Physiology. Deloach.O. Nature. Methods in Enzymology. hyperphenyl.Eichler et. 40. hyperarginiaemia.Goldman.alaninaemia and kidney failure are only few examples of metabolic disorders that can be treated by administration of enzymes.. Methods in Enzymology. 1987. Pharm. 32. Sometimes it is desirable to decrease the level of circulating metabolites that can enter erythrocytes. D. J. 149. Entry of Ferritin into Human Red Cells during Hypotonic Haemolysis. Delivery of Antiviral Agents: Several reports are available in the literature for the antiviral agents encapsulated in the resealed erythrocytes for effective delivery and targeting. G. 4. 1984. 1987. Recent Advances in Drug Delivery.DeLoach. Tsong.R. 5. Survival of Sucrose-Loaded Erythrocytes in the Circulation. 643–645. environmental. Biochem. 7. Lewis.235. lysosomal storage disorders such as Gaucher’s disease.. New York. 1987. Jaitely et al.2. Clin. This process is achieved by modifying a reverse-phase evaporation technique. b) Erythrosomes 51 These are specially engineered vesicular systems that are chemically cross-linked to human erythrocytes’ support upon which a lipid bilayer is coated. Biochem.A. 34. Activation of Phospholipase A2 by Adriamycin in vitro. This led to a complex that is more active than free DNR both in vitro and in vivo.pharm. Therapeutic Efficacy of Asparaginase Encapsulated in Intact Erythrocytes. and C. 1978. In Vivo Clearance of Antibody-Sensitized Human Drug Carrier Erythrocytes.jain. 300– 303. Table 6: Resealed erythrocytes used in delivery of enzymes Name of Enzymes L-Asparaginase Aminolevulinate dehydratase Purpose For treatment of leukemia To treat adolescent patient suffering from lead poisoning. R. 10. Pharm. K.Ihler. 49 ferromagnetic colloid compound 18. Lewis. Kinosita and T. Carrier Erythrocyte.. Ropars.Facchinetti. 1997.1008-1012 iii) Erythrocytes as Circulating Bioreactors Erythrocytes have been realized as carriers for enzymes to serve as circulating bioreactors. Moreover. / Journal of Pharmacy Research 2009. hyperuricaemia. Towards Cellular Drug Targeting and Controlled Release of Drugs by Magnetic Fields. 1979. M..G. since nanoerythrosomes are particles. 2.Therapeutical possibilities of Drug Encapsulate in Erythrocytes. 424–425. 589–594. 8. 12. 2(6). 230.R. 677. Biophys. Acta.L.A. myo-[3H]-inositol loaded erythrocytes and white ghosts: Two models to investigate the phosphatidylinositol synthesis in human red cells. 6. Reference 44 45 9.A. Alpar and D.59.137-146 U. 14.K. M.Bach.trans. Novel approaches a) Nanoerythrosomes 50 An erythrocyte based new drug carrier. Academic Press.A. 243–250... Sci. antimicrobial drug and vitamins and steroids. Adv. 669-672 V. J. P.tajerzadeh.June 2009 1011 . 496:136. Journal of Pharmacy Research Vol. A. U. 1986.biochemistry soc.R. Pharmacol. Academic Press. R. Biophys. 11-15. Indian J. Erythrocytes have also been used as circulating bioreactors for the controlled delivery of antiviral drugs. 1976. 2003.O.chassaigne. 19.Alpar. 153-200. Carrier Erythrocyte an Overview. R. Biosci. 272. D. v) Erythrocytes as Carriers for Enzymes Enzymes can be injected into the blood stream to replace a missing or deficient enzyme in metabolic disorders or to degrade toxic compounds accumulated in the blood due to a disease likewise.Issue 6.22. 1967. Summers.J.67. 257–261. Table 5: Resealed erythrocytes for delivery of antiviral drugs Categories of Drugs Name of drugs Azidothymidine Azidothymidine Derivative homodinucleotideloaded erythrocytes Deoxycytidine Antiviral nucleotide Derivatives analogues Azathioprene and Acyclovir Derivatives Reference Purpose 41 Slow delivery of the antiretro viral drug azidothymidine 42 Encapsulated into erythrocytes for targeting to macrophages Heterodinucleotide 43 Selective delivery to of azidothymidine and acyclovir macrophage for protection against Human Immunodeficiency Virus or Herpes Simplex Virus been developed which is prepared by extrusion of erythrocyte ghosts to produce small vesicles having an average diameter of 100 nm. Advance in the bioscience.DeLoach. 215.C. 258–260.M. Pharm. 15. phagocytosis may be involved in their mechanism of potentiation. EP Goldberg. J. Daunorubicin (DNR) was covalently conjugated to the nEryt (nErytDNR) using glutaraldehyde as homobifunctional linking arm. Sprandel.. Cellular Drug-Carrier System and Their Possible Targeting in Targeted Drug. G. S. 1979..Shintizky. These vesicles have been proposed as useful encapsulation systems for macromolecular drugs. Encapsulation of PEG-Urease/PEG-AlaDH Within Sheep Erythrocytes and Determination of the System’s Activity in Lowering Blood Levels of Urea in Animal Models .Y. Baker.Harris and G. Int. Ed. Nature. Resealed Erythrocytes: Drug Carrier Potentials and Biomedical Applications. C.. M. T. M. D.R. San Diego. J. 223-231. J. 10.Ryman. 1983.P. 67. Engineered Erythrocytes as a Drug Delivery System. J. Advance in Bioscicence.Jain and N. 67.al. H. 9-20.Lewis and H. Green and K. 21.Tyrrell.1984.Zimmermann. 1985. 275-281.Nicolau. An Erythrocyte Encapsulator Dialyzer Used in Preparing Large Quaitatities of Erythrocyte ghost 3. 17.J. 384–385. Acta. Indian Drugs. R. 1996.Ihler. Ther. 1987. Derrickson. Widder. H. 13. Daunorubicin (DNR) conjugated to these nanoerythrosomes has a higher antineoplastic index than the free drug. D. named nanoerythrosome has 20. In Vitro Drug Release from Human Carrier Erythrocyte AS Carrier System. Pharmacol.M. Hamidi and H. Patel et al. 10. REFERENCES: 1. Eichler et al.Raz. 512:254. vi) Erythrocytes as Carriers for Proteins and Macromolecules: 34 Table 7: Resealed erythrocytes used in delivery of proteins and macromolecules Name of Proteins Insulin Mycotoxins Purpose Reference For its sustained release 46 For specific delivery of this highly toxic 47 proteins to liver macrophages recombinant human A cellular sustained delivery system 48 erythropoietin (rHuEpo) for in vivo administration Aspirin and Prevention of thromboembolism.4. Tortara B. (Series). Role of Drug. 16. 11. 1987. 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