Research Article Cite This: ACS Appl. Mater. Interfaces 2018, 10, 1556−1565
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Multifunctional PHPMA-Derived Polymer for Ratiometric pH Sensing, Fluorescence Imaging, and Magnetic Resonance Imaging Fengyu Su,†,⊥ Shubhangi Agarwal,‡,⊥ Tingting Pan,§,∥,⊥ Yuan Qiao,§ Liqiang Zhang,† Zhengwei Shi,† Xiangxing Kong,† Kevin Day,† Meiwan Chen,∥ Deirdre Meldrum,*,† Vikram D. Kodibagkar,*,‡ and Yanqing Tian*,§ †
Center for Biosignatures Discovery Automation, Biodesign Institute, Arizona State University, Tempe, Arizona 85287, United States School for Biological and Health Systems Engineering, Arizona State University, Tempe, Arizona 85281, United States § Department of Materials Science and Engineering, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China ∥ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Avenida da Universidade, Taipa, Macau 999078, China
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S Supporting Information *
ABSTRACT: In this paper, we report synthesis and characterization of a novel multimodality (MRI/fluorescence) probe for pH sensing and imaging. A multifunctional polymer was derived from poly(N-(2hydroxypropyl)methacrylamide) (PHPMA) and integrated with a naphthalimide-based-ratiometric fluorescence probe and a gadolinium− 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex (Gd− DOTA complex). The polymer was characterized using UV−vis absorption spectrophotometry, fluorescence spectrofluorophotometry, magnetic resonance imaging (MRI), and confocal microscopy for optical and MRI-based pH sensing and cellular imaging. In vitro labeling of macrophage J774 and esophageal CP-A cell lines shows the polymer’s ability to be internalized in the cells. The transverse relaxation time (T2) of the polymer was observed to be pH-dependent, whereas the spin-lattice relaxation time (T1) was not. The pH probe in the polymer shows a strong fluorescence-based ratiometric pH response with emission window changes, exhibiting blue emission under acidic conditions and green emission under basic conditions, respectively. This study provides new materials with multimodalities for pH sensing and imaging. KEYWORDS: polymer, pH sensor, ratiometric sensor, MRI, fluorescence imaging, dual-modality
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INTRODUCTION Cellular pH (intracellular and extracellular) plays a critical role in cellular metabolism, immune function, cell metastasis, and calcium signaling. Intracellular pH is heterogeneous because of the different functions of the various organelles, ranging from 4.5 in lysosome to 8.5 in mitochondria with an average around 7.4.1,2 The heterogeneity of pH in organelles, cells, tissues, and organs is critical in maintaining cell functions and pH homeostasis, and cellular pH alterations are indicative of cell function changes and pathologies such as ischemia, chronic obstructive pulmonary disease, renal failure, and cancer.3 Extracellular pH is normally neutral around 7.2 and both the intracellular and extracellular pH values regulate the function of each other. Low extracellular pH (
