Inhibitory prodrug mechanism for cysteine cathepsin-targeted self-controlled drug release

Abstract

Tumour-associated macrophages (TAMs) support tumour development and have emerged as important regulators of therapeutic response to cytostatic agents. To target TAMs, we have developed a novel drug delivery approach which induces drug release as it inhibits cysteine cathepsin activity. This inhibitory prodrug (IPD) approach establishes a self-regulated system where drug release stops after all cysteine cathepsins are inhibited. This could improve the therapeutic window for drugs with severe side effects. We demonstrate and characterise this self-regulation concept with a fluorogenic IPD model. Next, we applied this IPD strategy to deliver cytotoxic drugs, as doxorubicin and monomethyl auristatin E, which are efficiently released and dose-dependently eliminate RAW264.7 macrophages. Lastly, by exploiting the increased cathepsin activity in TAM-like M2-polarised primary macrophages, we show that IPD-Dox selectively eliminates M2 over M1 macrophages. This demonstrates the potential of our IPD strategy for selective drug delivery and modulation of the tumour microenvironment.

Graphical Abstract

Keywords:

• Inhibitory prodrug
• selective drug delivery
• cysteine cathepsins
• tumour-associated macrophages
• tumour microenvironment

Acknowledgements

The authors are thankful to Camille M. le Gall for the help with obtaining mouse bone marrow.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

M.V. is recipient of ERC Starting grant CHEMCHECK (679921) and a Gravity Program Institute for Chemical Immunology tenure track grant by NWO.