TY - JOUR
T1 - Activatable Water-Soluble Probes Enhance Tumor Imaging by Responding to Dysregulated pH and Exhibiting High Tumor-to-Liver Fluorescence Emission Contrast
AU - Xiong, Hu
AU - Kos, Petra
AU - Yan, Yunfeng
AU - Zhou, Kejin
AU - Miller, Jason B.
AU - Elkassih, Sussana
AU - Siegwart, Daniel J.
N1 - Funding Information:
D.J.S. gratefully acknowledges financial support from the Welch Foundation (I-1855) and the Cancer Prevention and Research Institute of Texas (CPRIT) (R1212). J.B.M. acknowledges CPRIT (RP140110) for fellowship support. S.E. acknowledges the National Science Foundation (NSF) (GRFP 1000198224) for fellowship support. We also acknowledge the UT Southwestern Live Cell Imaging Facility, a Shared Cancer Center Resource supported by an NCI Cancer Center Support Grant (1P30 CA142543-05).
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/20
Y1 - 2016/7/20
N2 - Dysregulated pH has been recognized as a universal tumor microenvironment signature that can delineate tumors from normal tissues. Existing fluorescent probes that activate in response to pH are hindered by either fast clearance (in the case of small molecules) or high liver background emission (in the case of large particles). There remains a need to design water-soluble, long circulating, pH-responsive nanoprobes with high tumor-to-liver contrast. Herein, we report a modular chemical strategy to create acidic pH-sensitive and water-soluble fluorescent probes for high in vivo tumor detection and minimal liver activation. A combination of a modified Knoevenagel reaction and PEGylation yielded a series of NIR BODIPY fluorophores with tunable pKas, high quantum yield, and optimal orbital energies to enable photoinduced electron transfer (PeT) activation in response to pH. After intravenous administration, Probe 5c localized to tumors and provided excellent tumor-to-liver contrast (apparent T/L = 3) because it minimally activates in the liver. This phenomenon was further confirmed by direct ex vivo imaging experiments on harvested organs. Because no targeting ligands were required, we believe that this report introduces a versatile strategy to directly synthesize soluble probes with broad potential utility including fluorescence-based image-guided surgery, cancer diagnosis, and theranostic nanomedicine.
AB - Dysregulated pH has been recognized as a universal tumor microenvironment signature that can delineate tumors from normal tissues. Existing fluorescent probes that activate in response to pH are hindered by either fast clearance (in the case of small molecules) or high liver background emission (in the case of large particles). There remains a need to design water-soluble, long circulating, pH-responsive nanoprobes with high tumor-to-liver contrast. Herein, we report a modular chemical strategy to create acidic pH-sensitive and water-soluble fluorescent probes for high in vivo tumor detection and minimal liver activation. A combination of a modified Knoevenagel reaction and PEGylation yielded a series of NIR BODIPY fluorophores with tunable pKas, high quantum yield, and optimal orbital energies to enable photoinduced electron transfer (PeT) activation in response to pH. After intravenous administration, Probe 5c localized to tumors and provided excellent tumor-to-liver contrast (apparent T/L = 3) because it minimally activates in the liver. This phenomenon was further confirmed by direct ex vivo imaging experiments on harvested organs. Because no targeting ligands were required, we believe that this report introduces a versatile strategy to directly synthesize soluble probes with broad potential utility including fluorescence-based image-guided surgery, cancer diagnosis, and theranostic nanomedicine.
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U2 - 10.1021/acs.bioconjchem.6b00242
DO - 10.1021/acs.bioconjchem.6b00242
M3 - Article
C2 - 27285307
AN - SCOPUS:84979590909
SN - 1043-1802
VL - 27
SP - 1737
EP - 1744
JO - Bioconjugate Chemistry
JF - Bioconjugate Chemistry
IS - 7
ER -