Boronated Dendrimers Linked to Monoclonal Antibodies 6521 Boron Clusters Directly Linked to mAb

Monoclonal antibodies (mAb) have been attractive targeting agents for delivering radionuclides,45 drugs,46-50 toxins,51 and boron to tumors.52-55 Prior to the introduction of dendrimers as boron carriers, boron compounds were directly attached to mAbs.53,54 It has been calculated that

FIGURE 6.2 Structure of a boronated PAMAM dendrimer that has been linked to targeting moieties. PAMAM dendrimers consist of a core, repeating polyamido amino units, and reactive terminal groups. Each successively higher generation of PAMAM dendrimer has a geometrically incremental number of terminal groups. Boronated dendrimers have been prepared by reacting them with water-soluble isocyanato polyhedral boranes and subsequently attaching them to targeting moieties by means of heterobifunctional linkers.

FIGURE 6.2 Structure of a boronated PAMAM dendrimer that has been linked to targeting moieties. PAMAM dendrimers consist of a core, repeating polyamido amino units, and reactive terminal groups. Each successively higher generation of PAMAM dendrimer has a geometrically incremental number of terminal groups. Boronated dendrimers have been prepared by reacting them with water-soluble isocyanato polyhedral boranes and subsequently attaching them to targeting moieties by means of heterobifunctional linkers.

approximately 109 10B atoms per cell (approximately 20 mg/g tumor) must be delivered to kill tumor cells.55'56 Based on the assumption of 106 antigenic receptor sites per cell, approximately 50100 boron cage structures of carboranes, or polyhedral borane anions and their derivatives must be linked to each mAb molecule to deliver the required amount of boron for NCT. The attachment of such a large number of boron cages to a mAb may result in precipitation of the bioconjugate or a loss of its immunological activity. Solubility can be improved by inserting a water-soluble gluco-namide group into the protein-binding boron cage compounds, thereby enhancing their water solubility.57 This modification makes it possible to incorporate up to 1100 boron atoms into a human gamma globulin (HGG) molecule without any precipitation. Other approaches to enhance solubility include the use of negatively charged carboranes58 or polyhedral borane anions,59 as well as the insertion of carbohydrate groups.60,61 A major limitation of using an agent containing a single boron cage is that a large number of sites must be modified to deliver 103 boron atoms per molecule of antibody and this can reduce its immunoreactivity activity. Alam et al. showed that attachment of an average of 1300 boron atoms to mAb 17-1A, which is directed against human colorectal carcinoma cells, resulted in a 90% loss of its immunoreactivity.62

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