Concerted Activation of Photosensitizers and Release of Anticancer Drugs Through Tetrazine-Induced Bioorthogonal Decaging Reactions

Project: Research

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Photodynamic therapy is a promising and minimally invasive therapeutic modality for cancer. It requires a photosensitizer, light of appropriate wavelength, and molecular oxygen to induce a series of photochemical reactions, resulting in generation of reactiveoxygen species (ROS) to eradicate cancer cells. Over the past decade, there has been considerable interest in exploring effective means for targeted delivery of photosensitizers. Conjugation with tumor-targeting ligands, such as monoclonal antibodies, tumor-homing peptides, and folate is one of the most common strategies. This approach, however, has intrinsic limitations, such as the tedious procedure of bioconjugation and the uncertain expression levels of cellular receptors due to the heterogeneity of cancer cells. The steric hindrance exerted by the photosensitizers may also alter the configuration of and affect the binding with the targeting domains. As another promising approach to confine the photodynamic action at the tumor, activatable photosensitizers have also been actively explored. These smart therapeutic agents are quenched in the native state either by the neighboring quencher or via the selfquenching mechanism. Upon activation by cancer-related stimuli, such as the acidic and thiol-enriched tumor microenvironment and tumor-associated proteases and mRNA, the photoactivities of the photosensitizers are restored. However, certain cleavable linkers have been proven to be unstable in circulation, leading to premature activation of the photosensitizers before being delivered to the desired site. Moreover, the concentration of endogenous stimuli may vary in different types of tumors. To circumvent some of thesedrawbacks, we plan to utilize bioorthogonal chemistry to achieve tumor targeting, specific activation of photosensitizers, and controlled release of anticancer drugs simultaneously. We will first prepare a series of boron dipyrromethene (BODIPY)-basedphotosensitizers functionalized with a 3-isocyanopropyl group as a removable bioorthogonal component and an anticancer drug through a self-immoative 2,6-bis (hydroxymethyl)-p-cresol platform. The meso-position of the BODIPYs is caged withan ester group, which can inhibit their fluorescence emission and ROS generation. The 3-isocyanopropyl unit of these conjugates will then be subject to [4+1] cycloaddition with tetrazine moieties which have been tagged on cancer cells through conjugation totumor-targeting antibodies or peptides. After site-specific ligation and a cascade of disassembling reactions, the photosensitizers will be activated by removing the mesoester protecting group and the anticancer drugs will be released to induce an additionalchemocytotoxic effect. These bioorthogonal decaging reactions leading to specific activation of photosensitizers and controlled release of anticancer drugs will be validated in a range of cancer cells and tumor-bearing nude mice.


Project number9043022
Grant typeGRF
Effective start/end date1/01/21 → …