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Int. J. Mol. Sci. 2018, 19(6), 1646; https://doi.org/10.3390/ijms19061646

LAT1-Targeting Thermoresponsive Fluorescent Polymer Probes for Cancer Cell Imaging

1
Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8012, Japan
2
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan
*
Authors to whom correspondence should be addressed.
Received: 16 April 2018 / Revised: 24 May 2018 / Accepted: 25 May 2018 / Published: 1 June 2018
(This article belongs to the Special Issue Smart Polymers for Biomedical Applications)
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Abstract

L-type amino acid transporter 1 (LAT1) is more highly expressed in cancer cells compared with normal cells. LAT1 targeting probes would therefore be a promising tool for cancer cell imaging. In this study, LAT1-targeting thermoresponsive fluorescent polymer probes based on poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (P(NIPAAm-co-DMAAm)) were synthesized and their affinity for LAT1 was evaluated. The synthesized polymer probes interacted with LAT1 on HeLa cells, and inhibition of l-[3H]-leucine, one of the substrates for LAT1 uptake, was investigated. l-Tyrosine-conjugated P(NIPAAm-co-DMAAm) inhibited the uptake of l-[3H]-leucine, while P(NIPAAm-co-DMAAm) and l-phenylalanine-conjugated P(NIPAAm-co-DMAAm) did not. This result indicated that l-tyrosine-conjugated polymer has a high affinity for LAT1. The fluorescent polymer probes were prepared by modification of a terminal polymer group with fluorescein-5-maleimide (FL). Above the polymer transition temperature, cellular uptake of the polymer probes was observed because the polymers became hydrophobic, which enhanced the interaction with the cell membrane. Furthermore, quantitative analysis of the fluorescent probe using flow cytometry indicated that l-tyrosine-conjugated P(NIPAAm-co-DMAAm)-FL shows higher fluorescence intensity earlier than P(NIPAAm-co-DMAAm)-FL. The result suggested that cellular uptake was promoted by the LAT1 affinity site. The developed LAT1-targeting thermoresponsive fluorescent polymer probes are expected to be useful for cancer cell imaging. View Full-Text
Keywords: poly(N-isopropylacrylamide); fluorescent polymer probe; L-type amino acid transporter 1 targeting poly(N-isopropylacrylamide); fluorescent polymer probe; L-type amino acid transporter 1 targeting
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Matsuura, M.; Ohshima, M.; Hiruta, Y.; Nishimura, T.; Nagase, K.; Kanazawa, H. LAT1-Targeting Thermoresponsive Fluorescent Polymer Probes for Cancer Cell Imaging. Int. J. Mol. Sci. 2018, 19, 1646.

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