Prodrug, dendritic

We decided to apply the elimination-based dendritic system to the synthesis of an anticancer prodrug and to evaluate it in a tumor cell cytotoxicity assay. Dendritic prodrugs 20 and 21 were synthesized with the chemotherapeutic drug melphalan as a tail unit and a trigger that is activated by PGA (Fig. 5.14). 

FIGURE 5.14 Chemical structures of AB3 self-immolative dendritic prodrugs with melpha-lan tail units and a trigger that is activated by PGA. (See the color version of this figure in Color Plates section.)... 

Then, we evaluated the enzymatic activation of a second-generation dendritic prodrug with camptothecin (CPT), an anticancer agent, in place of the reporter groups (dendron 38). 

FIGURE 5.33 Molecular structure of second-generation, self-immolative, dendritic CPT prodrug with a trigger designed for activation by PGA. 

FIGURE 5.34 CPT release from dendritic prodrug 38 with PGA ( ) and without PGA ( ). 

FIGURE 5.35 Growth inhibition assay of three human cancerous cell lines, with dendritic prodrug 38 in the presence ( ) and absence ( ) of PGA cells were incubated for 72 h. 

Shamis, M. Lode, H. N. Shabat, D. Bioactivation of self-immolative dendritic prodrugs by catalytic antibody 38C2. J. Am. Chem. Soc. 2004, 126, 1726-1731. 

Gopin, A. Ebner, S. Attali, B. Shabat, D. Enzymatic activation of second-generation dendritic prodrugs conjugation of self-immolative dendrimers with poly(ethylene glycol) via click chemistry. Bioconj. Chem. 2006, 17, 1432-1440. 

J. Pan, L. Ma, B. li, Y. li, L. Guo, Novel dendritic naproxen prodrugs with poly (asparhc add) ohgopephde synthesis and hydroxyapatite binding in vitro, Synth. Commun. 42 (2012) 3441-3454. 

As an example of a selectively acting drug carrier, we would like to mention also the PDEPT (polymer-directed enzyme prodrug therapy) approach based on combination of HPMA copolymer prodrug with the poly(HPMA)-enzyme conjugate selectively generating the cytotoxic drug within tumor. As an example a combination of PKl and polymer-cathepsin B system can be cited but also other combinations were tested. HPMA-based polymers with a micellar or dendritic structure have been also intensively studied they are described in separate chapters. 

Similar approaches have also been used in the field of dendritic polymers. Calderon et al. (2009) prepared polymer-drug conjugates from dendritic polyglycerol and maleimide-bearing prodrugs (Tyagarajan et al., 2003 ... 

Calderon, M., Graeser, R., Kratz, F. and Haag, R. (2009) Development of enzymatically cleavable prodrugs derived from dendritic polyglycerol. Bioorg Med Chem Lett, 19,3725-3728. 

The best results for the dendritic compounds were obtained with a heterodimeric prodrug. Toxicity for prodrug 36, constructed of DOX and CPT, was about 50-fold higher than the activity measured using a combination of two monomeric prodrugs (34a and 35a) when bioactivation was performed. 

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