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Exploiting metabolic acidosis in solid cancers using a tumor-agnostic pH-activatable nanoprobe for fluorescence-guided surgery

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-16814-4

2041-1723

Floris J. Voskuil, Pieter J. Steinkamp, Tian Zhao, Bert van der Vegt, Marjory Koller, Jan J. Doff, Yalia Jayalakshmi, Jeffrey P. Hartung, Jinming Gao, Baran D. Sumer, Max J. H. Witjes, Gooitzen M. van Dam, Yasser Saud O Albaroodi, Lukas B. Been, Feike A. Dijkstra, Boudewijn van Etten, Qianjin Feng, Robert J. van Ginkel, Kirsten Sundby Hall, Klaas Havenga, Jan Willem Haveman, Patrick Hemmer, Liesbeth Jansen, Steven J. de Jongh, Gürsah Kats‐Ugurlu, Wendy Kelder, Schelto Kruijff, I G Kruithof, Ellen J. Van Loo, Jan L.N. Roodenburg, Niraj Shenoy, Kees‐Pieter Schepman, Sebastiaan A. H. J. de Visscher,

Medical Imaging Techniques and Applications

Cancer cell metabolism leads to a uniquely acidic microenvironment in solid tumors, but exploiting the labile extracellular pH differences between cancer and normal tissues for clinical use has been challenging. Here we describe the clinical translation of ONM-100, a nanoparticle-based fluorescent imaging agent. This is comprised of an ultra-pH sensitive amphiphilic polymer, conjugated with indocyanine green, which rapidly and irreversibly dissociates to fluoresce in the acidic extracellular tumor microenvironment due to the mechanism of nanoscale macromolecular cooperativity. Primary outcomes were safety, pharmacokinetics and imaging feasilibity of ONM-100. Secondary outcomes were to determine a range of safe doses of ONM-100 for intra-operative imaging using commonly used fluorescence camera systems. In this study (Netherlands National Trial Register #7085), we report that ONM-100 was well tolerated, and four solid tumor types could be visualized both in- and ex vivo in thirty subjects. ONM-100 enables detection of tumor-positive resection margins in 9/9 subjects and four additional otherwise missed occult lesions. Consequently, this pH-activatable optical imaging agent may be clinically beneficial in differentiating previously unexploitable narrow physiologic differences.