Polyelectrolyte nanocomplex formation of heparin-photosensitizer conjugate with polymeric scavenger for photodynamic therapy

• The anionic heparin-pheophorbide a (HPhA) conjugate was synthesized.
• The cationic polyethylenimine-β-carotene (PCAR) conjugate was synthesized.
• Nanocomplex was prepared via the ionic interaction between HPhA and PCAR.
• Controllable production of 1O2 can be performed using the HPhA/PCAR nanocomplex.
• The HPhA/PCAR nanocomplex could be a new activatable PS platform for selective PDT.

A polyelectrolyte nanocomplex was prepared via the ionic interaction between the anionic heparin-pheophorbide a (HPhA) conjugate, which served as a water-soluble polysaccharide photosensitizer (PS), and the cationic polyethylenimine (PEI)-β-carotene (PCAR) conjugate, which served as a polymeric scavenger. This nanocomplex was designed to improve the water solubility and tumor specificity of PhA and to only release singlet oxygen at the tumor cell. A stable 150 nm-sized nanocomplex could be formed in the weight ratio range (PCAR/HPhA) of 0.3–0.5 in an aqueous environment. The PCAR scavenger significantly diminished the generation of active singlet oxygen from HPhA in a buffer solution. Singlet oxygen scavenging activity was lost only when HPhA and PCAR were separated from each other due to the dissociation of the complex nanostructures. It was confirmed that HPhA itself has neither colloidal properties nor a decrease in its ability to produce singlet oxygen. At the same time, the HPhA/PEI complex produced singlet oxygen in response to light. In a cell culture system, the cytotoxicity of the HPhA/PCAR nanocomplex toward cancer cells was greatly enhanced due to the efficient generation of singlet oxygen under light irradiation; this finding implies that the scavenging activity of PCAR can be restricted to intracellular environments. These results suggest that the HPhA/PCAR nanocomplex could provide a new activatable PS platform that facilitates more accurate and reliable photodynamic therapy (PDT) with site-specific and controllable production of singlet oxygen to be used for the treatment of cancer.