Bioreducible branched polyethyleneimine derivatives physically loaded with hydrophobic pheophorbide A: preparation,...

Branched-type hydrophilic polyethyleneimine derivatives (i.e., bPEI derivatives) are developed polymeric carriers for photodynamic therapy. Their chemical structures which contain pH-tunable hydrophobic/hydrophilic cavities enable efficient loading of hydrophobic drugs in basic pH environments. Intracellular stimuli trigger the release of the loaded drugs in bPEI derivatives. As expected, the hydrophobic photosensitizer known as pheophorbide A (PheoA) is solubilized by physical loading in the inner hydrophobic spaces of bPEI derivatives in environments with basic pH values. Interestingly, acidic pH environments induce aggregation, resulting in poor release of the loaded PheoA as well as in quenched photo-activity of the PheoA-loaded polymers. However, when reducible polycation derivatives of bPEI are used (i.e., RPC-bPEI), intracellular thiols degrade the disulfide linkages in the polymers, resulting in rapid PheoA release. Particularly, a RPC-bPEI containing 6 wt% PheoA (i.e., RPC-bPEI(0.8 kDa)-PheoA(6%)) respond remarkably well to light exposure and display large differences between dark toxicity and light-induced toxicity. Cellular uptake of RPC-bPEI(0.8 kDa)-PheoA(6%) is approximately sevenfold to ninefold lower than that of free PheoA. Nevertheless, the photo-toxicity of RPC-bPEI(0.8 kDa)-PheoA(6%) was only two- to sixfold less potent than that of free PheoA. These results suggest that reducible bPEI materials may act as potential solubilizers and carriers for low-molecular-weight hydrophobic anti-cancer drugs.