Journal
MOLECULAR PHARMACEUTICS
Volume 12, Issue 12, Pages 4237-4246Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.molpharmaceut.5b00430
Keywords
cancer imaging; fluorescence; small animal; tumor model; extracellular pH; pH-sensitive probe
Funding
- U.S. National Institutes of Health (NIH), NCI [P50 CA094056, R01 CA171651]
- NIBIB [R01 EB007276, R01 EB008111]
- National Science Foundation [CCF 0963742]
- Mr. and Mrs. Spencer T. Olin Fellowship
- NCI Ruth Kirschstein Fellowship [F30 CA189435]
- Medical Scientist Training Program at Washington University
- [S10 OD016237]
- [S10RR031625]
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Enhanced glycolysis and poor perfusion in most solid malignant tumors create an acidic extracellular environment, which enhances tumor growth, invasion, and metastasis. Complex molecular systems have been explored for imaging and treating these tumors. Here, we report the development of a small molecule, LS662, that emits near-infrared (NIR) fluorescence upon protonation by the extracellular acidic pH environment of diverse solid tumors. Protonation of LS662 induces selective internalization into tumor cells and retention in the tumor microenvironment. Noninvasive NIR imaging demonstrates selective retention of the pH sensor in diverse tumors, and two-photon microscopy of ex vivo tumors reveals significant retention of LS662 in tumor cells and the acid tumor microenvironment. Passive and active internalization processes combine to enhance NIR fluorescence in tumors over time. The low background fluorescence allows tumors to be detected with high sensitivity, as well as dead or dying cells to be delineated from healthy cells. In addition to demonstrating the feasibility of using small molecule pH sensors to image multiple aggressive solid tumor types via a protonation-induced internalization and retention pathway, the study reveals the potential of using LS662 to monitor treatment response and tumor-targeted drug delivery.
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