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

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 inhibito...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2022-12, Vol.37 (1), p.2566-2573
Main Authors: van Dalen, Floris J., Verdoes, Martijn
Format: Article
Language:English
Subjects:
Antibiotics
Bone marrow
Cancer therapies
Cathepsins
Cysteine
cysteine cathepsins
Cytostatic agents
Cytotoxicity
Doxorubicin
Drug delivery
Drug dosages
Enzymes
Growth factors
Immunology
Inhibitory prodrug
Life sciences
Macrophages
Microenvironments
Original
Pharmaceutical sciences
Phenols
Prodrugs
selective drug delivery
Tumor microenvironment
Tumors
tumour microenvironment
tumour-associated macrophages
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Summary: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.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2022.2122961