Palette of polarity-tunable halogenated bacteriochlorins for efficient photodynamic therapy in cellular and animal models

Abstract

We have previously reported the development of a telodendrimer, comprised of dendritic cholic acids and a linear polyethylene glycol (PEG), that can selfassemble and encapsulate hydrophobic chemotherapeutic drugs to form 25 to 50nm micellar-based nanoparticles. Using a highly efficient onebead-one-compound (OBOC) combinatorial technology, we have discovered several peptidic ligands that target cancer cell surface receptorswith high affinity and specificity. Such ligands can be easily conjugated to the telodendrimers via click chemistry, such that the ligands are displayed on the surface of the nanoparticles for efficient in vivo tumor targeting and intracellular drug delivery. Recently, we have developed a hybrid telodendrimer comprised of PEG, cholic acid and pyropheophorbibe. Like our standard telodendrimers, such hybrid telodendrimer can also self-assemble and efficiently encapsulate hydrophobic drugs to from 25 to 30nm nanoparticles. Such nanoporphyrin has proven to be extremely potent photosensitizer for in vivo phototherapy in both transgenic and xenograft tumor models. In addition to efficiently generate reactive oxygen species when illuminated with light, heat can also generated, thus allowing simultaneous photodynamic and photothermal therapy. In addition, we have discovered that low dose doxorubicin and/or heat shock protein inhibitor can be efficiently loaded into nanoporphyrin and greatly enhance the phototherapeutic effects. Clinical applications of nanoporphyrins include phototherapy of superficial tumors such as oral cancer and bladder cancer, and intraoperative phototherapy. Furthermore, nanoporphyrin can also be loaded with Gd(III) for MRI and Cu-64 for PET, making it a highly versatile theranostic agent.