In Vivo Bioorthogonal Chemistry Enables Local Hydrogel and Systemic Pro-Drug To Treat Soft Tissue Sarcoma

Abstract

The ability to activate drugs only at desired locations avoiding systemic immunosuppression and other dose limiting toxicities is highly desirable. Here we present a new approach, named local drug activation, that uses bioorthogonal chemistry to concentrate and activate systemic small molecules at a location of choice. This method is independent of endogenous cellular or environmental markers and only depends on the presence of a preimplanted biomaterial near a desired site (e.g., tumor). We demonstrate the clear therapeutic benefit with minimal side effects of this approach in mice over systemic therapy using a doxorubicin pro-drug against xenograft tumors of a type of soft tissue sarcoma (HT1080).

Dissociative Bioorthogonal Reactions

“…A remaining challenge is how to achieve a high enough concentration of the activator molecules at the site of disease. One such approach is the implantation of a hydrogel modified with reactive groups (Scheme A), as demonstrated with alginate hydrogels modified with tetrazines and doxorubicin prodrugs bearing trans ‐cyclooctene modifications . The authors injected the hydrogel adjacent to a sarcoma xenograft and intravenously administered repeat doses of the prodrug.…”

“…Reaction of the prodrug with the tetrazine‐modified hydrogel released doxorubicin locally. This approach cured sarcoma mice without detectable side effects . In contrast, systemic doxorubicin therapy did not improve survival and led to myelosuppression and weight loss.…”

The Emerging Role of Tetrazines in Drug‐Activation Chemistries

“…Recently, the authors showed that this TCO‐based release mechanism could also be used for masking esters and alcohols, while Pluth reported a thiocarbamate linkage that allowed the release of carbonyl sulfide as a gastrotransmitter . Finally, by linking tetrazines to an alginate‐containing hydrogel, TCO–doxorubicin conjugates were successfully activated in a mouse model . Work by Royzen demonstrated that tetrazines could be immobilised on magnetic iron oxide nanoparticles, thereby allowing the activation of TCO‐masked doxorubicin in MDA‐MB‐231 breast cancer cells (Scheme , below) …”

Alkene–Azide 1,3‐Dipolar Cycloaddition as a Trigger for Ultrashort Peptide Hydrogel Dissolution

“…Bioorthogonal chemical reactions that can be carried out in biological and physiological systems have been widely utilised in biological imaging, prodrug/protein decaging strategies and drug delivery . More recently, click reactions such as the strain‐promoted azide‐alkyne cycloaddition (SPAAC), oxime ligation and the inverse‐electron‐demand Diels–Alder (IEDDA) reaction between a trans ‐cyclooctene (TCO) and tetrazine have been utilised as a cross‐linker for hydrogels and as reservoirs for activation of TCO‐functionalised prodrugs (via an IEDDA reaction) . Truong and co‐workers recently used bioorthogonal reactions to promote the formation of hydrogels capable of controlled release by visible and UV light .…”