Protonation and Trapping of a Small pH-Sensitive Near-Infrared Fluorescent Molecule in the Acidic Tumor Environment Delineate Diverse Tumors in Vivo.
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.
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Rebecca C
RC
Gilson
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Rui
R
Tang
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Avik
A
Som
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Chloe
C
Klajer
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Pinaki
P
Sarder
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Gail P
GP
Sudlow
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Walter J
WJ
Akers
Departments of †Radiology, ‡Biomedical Engineering, and §Biochemistry & Molecular Biophysics, Washington University in St. Louis , St. Louis 63110, United States.
Samuel
S
Achilefu
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D019265:Spectroscopy, Near-Infrared / Q000379:methods; D059016:Tumor Microenvironment / Q000187:drug effects*
D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D054852:Small Molecule Libraries
cancer imaging; extracellular pH; fluorescence; pH-sensitive probe; small animal; tumor model