About Opportunity:

This new approach converts chemotherapy agents into prodrugs, significantly reducing systemic toxicity, and enabling local activation only at tumour sites where a specific catalyst, palladium, has been implanted. This offers the opportunity to significantly expand the therapeutic window for potent cytotoxics and expand treatment options for aggressive tumours, such as glioblastoma.

The Challenge

An important challenge limiting the efficacy of cancer chemotherapy drugs is their toxicity to healthy normal tissue. The significant side effect profile that many of these compounds have limits the effective doses that can be administered. One means to overcome this limitation is through a targeted pro-drug approach where the active form of the drug is a masked so that it is biologically inert and is activated to its toxic form only at the site of tumour. To achieve this, the prodrug form needs to have negligible pharmacological properties, but be readily cleavable in the presence of a suitable safe biologically inert catalyst present at the tumour site.

Technology

University of Edinburgh researchers have developed a method for generating a class of prodrugs that meet these criteria. The compounds are masked using a novel N-propargylation strategy that eliminates their cytotoxic properties. These prodrugs are readily activated in the presence of palladium, Pd(0), which rapidly catalyses the removal of the propargyl moiety and release of the fully active parent drug. By implanting an appropriate palladium source at the tumour site spatially controlled activation is achieved.

Exemplification Data

Significant in vitro data showing the applicability of this approach: prodrug versions of 5- fluorouracil and floxuridine that are stable and non-toxic; rapid activation in the presence of Pd(0); significant in vitro toxicity in a panel of cancer cell lines; ex vivo validation of Floxuridine prodrug in prostate cancer explants.

Development Status

Proof of principal data

Key Benefits:

• Repeated systemic administration is possible
• Cytotoxic activity is achieved locally only at tumour site
• Expands arsenal of chemotherapy agents available to treat tumours such as glioblastoma multiforme

Applications:

• Generation of prodrugs from heterocyclic compounds
• Oncology drug discovery and delivery
• Targeted therapeutics

IP Status:

Patent application (WO/2014/202994) covering methods, compounds and their uses.

Publications:

• Nature Communications (2014) (5) 3277
• Sci. Rep. (2015) 19 (5):9329

The University of Edinburgh is seeking commercial partners to license this technology and/or collaborate on further development of the technology for commercial use.