Dendrimer-didox nanocomplex for enhanced anticancer activity

Didox (DX; 3,4-dihydroxy benzo-hydroxamic acid), a derivative of hydroxamic acid, is a potent inhibitor of ribonucleotide reductase (RR), the enzyme responsible for deoxyribonucleotide synthesis. While RR inhibitors such as hydroxyurea and others are being used widely for cancer treatment, DX is emerging as a newer RR inhibitor because of its lower rate of hematopoietic toxicity. DX also has an antiretroviral activity as it can deplete deoxynucleotides necessary for the synthesis of the pro-viral DNA intermediates of retrovirus replication. Our group is working on investigating application of DX for the treatment of glioblastoma (GBM). Since DX alone cannot cross the blood-brain barrier (BBB) (Veale et al. Br J Cancer 58:70-72, 1988; Dogruel et al. J Neurochem 87(1):76-84, 2003; Sebastien et al. Drug Metab Dispos 34:1945-1949, 2006), we propose use of dendrimers as a delivery system to improve its uptake by the brain. We investigated many different approaches such as using different PAMAM dendrimers (G4-amine, G4-Pyrr, hybrid dendrimers), changing the dendrimer and DX concentrations. Amine and PYRR dendrimers were of 4-5-nm size range and hybrid dendrimers were of 7-9-nm size range. Results indicated that dendrimers enhance the cell penetration capability of DX in GBM cell lines (2D and 3D). Effect of dendrimer was more prominent in 3D (neurospheres) compared with that in 2D cell lines. Pyrrolidinone (PYRR) PAMAM dendrimer formulations showed better biocompatibility compared with amine PAMAM dendrimers. We have also used the hybrid dendrimer approach to manage the safety of amine dendrimers. It was observed that carboxylate dendrimer significantly helped reduce amine dendrimer toxicity in hybrid dendrimer.