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is the reason for its success. For example, BR96 binds to a tumor-associated antigen that is abundantly (greater than 200000 molecules per cell) expressed on human tumors [209]. Second, the ability of the conjugate to bind antigen, i.e. its immunoreactivity, was tested and found to be as effective as that of unconjugated BR96 [210]. Third, it was shown that conjugate immunoreactivity was predictive of the antigen-specific cytotoxic potency [211]. Fourth, the BR96-DOX conjugate is rapidly endocytosed after binding to the cell receptors [209,212]. Fifth, a heterobifunctional linker, 6-maleimidocaproylhydrazone of Doxorubicin, was synthesized that imparts an acceptable stability at neutral pH but rapidly releases Doxorubicin under acidic conditions that mimic those of the lysosomal environment [213]. Human trials now in progress with this novel immunoconjugate, which if successful, would open up a new drug delivery approach of vast potential. |
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3. Regulated Delivery to Satisfy Chronobiology |
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Chronobiology deals with physiological functions that exhibit prominent rhythmic change. The daily rhythm, known as circadian, has been studied most extensively although high-frequency (ultradian, menstrual, and seasonal) rhythms have been well documented. Circadian rhythms have been demonstrated for over 100 variables in the blood, urine, and saliva [214]. Circadian rhythms also exist for body temperature, blood pressure [215], heart rate [216], and the plasma concentration of hormones [217]. The pulsed secretion of hormones has been described for insulin [218], somatostatin [219], luteinizing hormone [220], and several other peptides [221223]. Many studies in a variety of pharmacological fields have shown a strong dependency of the onset of disease on circadian temporal rhythm. In asthmatics, episodes of dyspnea take place mainly between 2 and 7 a.m. and are 50-fold higher between 4 and 5 a.m. than between 4 and 5 p.m. [224]. Digestive tract rhythmicity has been described for many functions of the gastrointestinal tract, e.g. high gastric acid secretion rates in the evening hours and low in the morning hours [225,226]. Myocardial infarction [227], sudden cardiac death [228], thrombotic stroke [229], and arterial embolism [230] show a strong circadian rhythm with a morning peak and an evening trough. A circadian rhythm in all blood cell types has been well documented [231] including cells of the immune system such as B and T lymphocytes and natural killer cells [232234]. Circadian rhythms have also been demonstrated for lymphocyte proliferation [235], as well as CD3 and CD4 epitope molecules at their surface [235], which may relate to cell reactivity to antigen exposure and may be critical to the fight against malignancies and other immune diseases [237238]. Therefore, better management of patients could be obtained by including in the clinical protocol the application of the chronobiological aspects of the pathophysiology of the disease [239]. |
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