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<p>A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side
effects. Despite recent advances, this remains difficult to achieve in practice as most approaches
rely on biomarkers or physiological differences between malignant and healthy tissue, and thus
benefit only a subset of patients in need of treatment. To address this unmet need, we introduced
a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation
of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and
other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is
thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or
oxygen levels. The platform consists of a tetrazine-modified sodium hyaluronate-based
biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)-
modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is
captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction
between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site,
thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific
biomarkers of traditional targeted therapy. Here, TCO-modified protodrugs of four prominent
cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the
modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and
activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in
vivo studies. Studies in rodents show that a single injection of the tetrazine-modified biopolymer,
SQL70, efficiently captures SQP33 protodrug doses given at 10.8-times the maximum tolerated
dose of conventional doxorubicin with greatly reduced systemic toxicity.
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MGMT-Methylation in Non-Neoplastic Diseases of the Central Nervous System