Combating Hypoxic Tumors with Self-Assembled Nanophotosensitizers based on Biotinylated Nitric Oxide-Releasing Phthalocyanines
DescriptionPhotodynamic therapy (PDT) has emerged as a compelling treatment modality for a range of superficial and localized cancer. It involves the excitation of a photosensitizer through light irradiation followed by interactions with endogenous oxygen to generatereactive oxygen species, particularly singlet oxygen, to cause cellular damage in tumor. Because of this unique mechanism, PDT exhibits various inherent superiorities, including the non-invasive nature, fast healing process, no apparent drug resistance,and few side effects. However, there are still some hurdles to be addressed to promote its clinical translation. The treatment outcome of PDT depends largely on the tumor specificity of the photosensitizers and the oxygen concentration around the tumor. Toaddress the first issue, conjugation of photosensitizers with tumor-targeting ligands or control units that can activate the photosensitizers in the tumor microenvironment have been actively studied. For the second aspect, owing to the highly abnormal tumor microvasculature, tumor hypoxia is a common phenomenon, which is not favorable for PDT because of its oxygen-dependent nature. As a result, various approaches have been explored to improve the therapeutic efficacy of PDT against hypoxic tumors, including the use of oxygen carriers and in situ generation of oxygen through catalytic decomposition of hydrogen peroxide or reaction of peroxides with water. These approaches, however, still have some limitations, such as the tedious synthetic and fabrication protocols of the nanocarriers, low oxygen loading by the oxygen carriers, undesired reaction of peroxides with body fluids outside the tumor region, and the insufficient hydrogen peroxide level in tumor for in situ oxygen generation. In this proposal, we plan to design and synthesize a series of zinc(II) phthalocyanine-based photosensitizers substituted with a tumor-targeting biotin and different number of nitric oxide (NO)-releasing units that can self-assemble into nanoparticles in aqueous media. Upon biotin receptor-mediated endocytosis into cancer cells, the self-quenched phthalocyanine aggregates would be dissociated to restore the photosensitizingproperties. The high intracellular glutathione level will trigger the release of NO, which can suppress the mitochondrial respiration and adenosine triphosphate production, thereby sparing more oxygen for PDT. It is expected that these self-assemblednanophotosensitizing systems with tumor-targeting and activatable properties, as well as an ability to inhibit cell respiration can exhibit NO-promoted PDT, particularly for eradication of hypoxic tumors. Using these nanosystems that can release different amounts of NO, we will further elucidate the roles of this fantastic gas in PDT using a series of in vitro and in vivo experiments.
|Effective start/end date||1/01/23 → …|