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soluble polymer conjugates may be employed [21,175]. Particle filtration may be used to localize delivery to the lungs [176], but it is not always true that this localization targets the drug to the appropriate cells [177]. Many particles in the systemic circulation are rapidly cleared by the reticuloendothelial system (RES), specifically, the Kupffer cells of the liver [178]. The uptake or kinetics of uptake of these particles may be altered through surface coatings such as poly(oxyethylene) or poloxamers [179]. Water soluble macromolecular conjugates may include antibodies to target the conjugate, and then the drug may be released by lysosomal enzymes after being internalized into the cell [21,179]. Antibodies, lectins, rheoviruses, and immunotoxins are among the many strategies for targeting [180]. Gene therapy and antisense are clearly new therapeutic approaches requiring targeting. The difficulties in the analytical methodology have made quantitation difficult and kinetic/dynamic studies in this field are slow in coming. In the absence of analytical methodology, characterization by pharmacodynamic response can be so variable that drug development is risky until the results from large trials are obtained. The use of liposomes to deliver immunomodulators for cancer and antiviral therapy has been tested in several clinical trials [180]. |
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We now focus on targeting with antibodies. Targeting with antibodies became possible with the publication in 1975 by Kohler and Milstein [181] of information on how large amounts of monoclonal antibodies (MoAbs) could be produced against specific antigen after in vivo immunization with the same antigen. Thus unlimited quantities of monoclonal antibodies directed against specific cell surface receptors could be affirmed. This new weapon, the magic bullet, can then be directed on cell surface determinants present in tumor cells or other cells to be killed. The major advantage of targeting is that it delivers larger amounts of the toxic materials to the diseased site and smaller amounts to the healthy tissue. |
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Although MoAbs are cytotoxic themselves and can be used to kill cells, MoAbs linked to drugs and toxins are more effective. Many immunoconjugates of MoAbs with drugs, proteins, enzymes, and toxins have been produced [182184]. |
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Antigen specificity and the number of antigenic molecules per tumor cell are important for the adequate delivery of drug to kill the cell. Active drug will have to be released after the MoAb binding to kill the cell. Preferably, the immunoconjugate is endocytosed [185,186] where it can release its drug load by hydrolysis of the drug-MoAb linkage by low pH or by one of the lysosomal enzymes. |
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Conjugation through an intermediate carrier such as, dextran, poly L-glutamic acid, liposomes, and HPMA retains a higher degree of MoAb activity and much higher drug capacity [187190]. In addition to the preservation of drug and antibody activity, the MoAb/Carrier system can (a) be used to incor- |
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