Inhibitory Prodrug Approach for Selective Elimination of Immunosuppressive M2 Macrophages

Tumor associated macrophages (TAMs) support tumor 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 in response to inhibition of pro-tumor cysteine cathepsin activity. Such inhibitory prodrug (IPD) establishes a self-regulated delivery 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 this self-regulation concept with a fluorogenic IPD model. We have applied our IPD strategy to two cytotoxic agents, doxorubicin and monomethyl auristatin E, which could be efficiently released from the IPD scaffold to induce concentration dependent toxicity in RAW macrophages. Lastly, by taking advantage of the increased cathepsin activity in TAM-like M2 polarized bone marrow derived 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 tumor microenvironment.