ACS Nano, 2013, in press
Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo
We report in this study the complexation of the chemotherapeutic drug doxorubicin (DOX) with the novel 6th generation cationic poly-L-Lysine dendrimer (DM) (MW 8.162 KDa) which we previously reported to exhibit systemic anti-angiogenic activity in tumor-bearing mice. DOX-DM complexation was confirmed by florescence polarisation (FP) measurement, proton nuclear magnetic resonance (1H NMR) spectroscopy and by molecular modelling. Enhanced penetration of DOX-DM (at 1:10 molar ratio), compared to the free DOX, into prostate 3-D multicellular tumor spheroid (MTS) was confirmed by confocal laser scanning microscopy (CLSM). Furthermore, DOX-DM complexes achieved a significantly higher cytotoxicity in DU145 MTS system compared to the free drug, as shown by growth delay curves. Incubation of MTS with low DOX concentration (1μM) complexed with DM, led to a significant delay in MTS growth compared to untreated MTS or MTS treated with free DOX. DOX-DM complex retention was also achieved in Calu6 lung cancer xenograft model in tumor-bearing mice as shown by live whole animal fluorescence imaging. Therapeutic experiments in B16F10 tumor bearing mice have shown enhanced therapeutic efficacy of DOX when complexed to DM. This study suggests that the cationic poly-L-Lysine DM molecules studied here could, in addition to their systemic anti-angiogenic property, complex chemotherapeutic drugs as DOX and improve their accumulation and cytotoxicity into MTS and solid tumors in vivo. Such approach offers new capabilities for the design of combinatory anti-angiogenic/anti-cancer therapeutics.