Development of Highly Versatile Oxygen-evolving Self-assembled Nanophotosensitizers for Photodynamic Eradication of Hypoxic Tumor

Description

Photodynamic therapy (PDT) is a clinically approved treatment modality for a range of cancers. It requires a photosensitive drug, light of appropriate wavelength, and oxygen to induce a chain of photochemical reactions, resulting in the generation of cytotoxic reactive oxygen species (ROS). The therapeutic outcome depends largely on the tumor selectivity of the photosensitizers, their efficiency in generating ROS, and the oxygen concentration around the tumor. To address the first issue, activatable photosensitizers have been actively explored. Generally, these therapeutic agents are deactivated in the native form, but upon interactions with tumor-associated stimuli, such as certain proteases and the acidic and reducing tumor microenvironments, the fluorescence emission and ROS generation are restored. This approach can minimize the photodamage to normal cells and tissues. However, the oxygen-dependent nature of PDT still limits its clinical application against cancer, especially the hypoxic cancer. Recently, different approaches have been investigated to combat tumor hypoxia, including direct delivery of oxygen by oxygen carriers and in-situ oxygen generation through catalytic transformation of hydrogen peroxide to oxygen. In most of these systems, nanocarriers based on polymers, gold nanoparticles, mesoporous silica nanoparticles, or metal-organic frameworks are required, which usually involve tedious synthetic and fabrication protocols and have limited drug loading and potential toxicity to healthy tissues. As a potentially improved alternative, carrier-free self-assembled nanomedicines are of much current interest. In this proposal, we aim to develop such nanophotosensitizing systems for photodynamic eradication of hypoxic tumor. The proposed work includes the preparation of a series of glutathione-responsive phthalocyanine-based photosensitizers with a tumor-targeting ligand, followed by co-assembly with fluorenylmethyloxycarbonyl-protected amino acids and iron(III) chloride to form tumor, the photosensitizing properties of the photosensitizers will be restored to generate ROS upon light irradiation. As cancer cells usually have high concentration of hydrogen peroxide, it is expected that the encapsulated iron(III) ions will undergo catalase-like reaction with hydrogen peroxide to generate oxygen that can assist the photodynamic action at hypoxic cancer cells. To introduce an additional therapeutic action against hypoxic tumor, the hypoxia-inducible factor 1 inhibitor acriflavine will also be co-assembled into the nanodrugs which can block the pathways promoting the growth of tumor. It is believed that these self-assembled oxygen-replenishing nanophotosensitizing systems with tumor-targeting and activatable properties, as well as diverse cell-killing mechanisms can exhibit enhanced therapeutic efficacy against hypoxic tumor and overcome the current limitations of PDT.