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porate different drugs with minimal alterations, (b) protect the drug because of encapsulation with the polymeric matrix, (c) deliver substantially higher amounts of drug than single conjugates, and (d) enhance efficacy of targeting, e.g., up to 100 MoAbs can be attached to a single liposome [191]. |
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Although targeted therapy has exciting potential there are several technical problems that have to be overcome before commercial products can be developed. |
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Antibodies may undergo conformational changes after conjugation, reducing their ability to bind to cell surface receptors. |
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In vivo stability of the chemical linkages of immunoconjugates may not be adequate to preserve drug and antibody activity. |
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Binding of the antibody to cell receptors may cause antigenic modulation and shedding or internalization of the receptors making subsequent treatment useless. |
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Receptor molecules shed into plasma may bind to MoAbs before the conjugate has a chance to reach its target. |
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Conjugates should have the ability to cross through several membranes, including the vascular barrier, and be able to permeate through the tumor. |
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Repeat treatments may cause immunogenic reactions especially since human MoAbs are difficult to obtain. |
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Targeted therapy has been extensively studied for cancer therapy because the usage of chemotherapeutic drugs in the treatment of cancer patients is usually terminated by the toxic effects on normal cells. Thus MoAbs [192196], drug/MoAb conjugates [197201], and drug/inert carrier/MoAb conjugates [202204] have been investigated in cancer therapy. Cancer drugs such as doxorubicin, daunorubicin, and vindesine as well as ricin and diphtheria toxin have been used with varied success [205207]. Despite the high expectation, in vivo results have been rather disappointing probably due to the limitations mentioned above and the fact that (a) cancer cells are heterogeneous; if not all cells are recognized, some will survive and proliferate; (b) conjugates that are effective against a particular cancer in one patient may not be effective against the same type of cancer in another patient; (c) solid tumors are known to shed their receptors upon antigenic modulation rendering subsequent treatments useless; and (d) diffusion of the drug within the tumor can be problematic. |
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Recently some very encouraging studies have been presented from BR96-Doxorubicin conjugates [208]. BR96-DOX was evaluated against human lung adenocarcinoma, colon carcinoma, and breast carcinoma growing as subcutaneous transplants in athymic mice. Treatment with BR96-DOX consistently cured most mice bearing lung adenocarcinoma and colon carcinoma and complete and partial tumor regressions were produced in breast carcinomas. In contrast, DOX alone or DOX conjugated with nonbinding MoAbs did not show antitumor activity. Probably the care taken in the design of the conjugate |
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