Synthesis of an amphiphilic tetrazine derivative and its application as a liposomal component to accelerate release of encapsulated drugs |
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| Institution: | 1. Department of Biomolecular Recognition Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan;2. Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan;3. Photon Medical Research Center, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, Shizuoka 431-3192, Japan;4. Department of Biophysical Chemistry, Kobe Pharmaceutical University, 4-19-1 Motoyama Kitamachi, Higashinada-ku, Kobe 658-8558, Japan;1. Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-1192, Japan;2. Institute for Frontier Science Initiative, Kanazawa University, Kanazawa 920-1192, Japan;3. Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan;4. Graduate School of Science, Osaka University, Osaka 560-0043, Japan;5. Medical Radioisotope Application Group, Japan Atomic Energy Agency, Takasaki, 370-1292 Japan;1. Department of Patho-Functional Bioanalysis Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan;2. Medical Imaging Project, Corporate R&D Headquarters, Canon Inc., 3-30-2 Shimomaruko, Ohta-ku, Tokyo, 146-8501, Japan;3. Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan;4. Biomedical Imaging Research Center, University of Fukui, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan |
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| Abstract: | Tetrazine irreversibly reacts with dienophiles, and its derivatives find wide applications in the fields of biochemistry and biophysics. We have synthesized an amphiphilic tetrazine derivative (2-hexadecyl-N-(6-(6-(pyridin-2-yl)-1,2,4,5-tetrazine-3-yl)pyridin-3-yl)octadecanamide; 1), which has a hydrophilic tetrazine structure and hydrophobic alkyl chains. Liposomes composed of compound 1 and 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) (PTz-liposome) were prepared. In search of a new drug delivery system (DDS), we investigated the viability of inverse electron-demand Diels-Alder, a reaction between tetrazine and 2-norbornene, on the surface of the liposomes to change membrane fluidity and promote spatial and temporal controlled release of the encapsulated drugs. Compound 1 was synthesized with a yield of 71%. MS analysis after incubation of 2-norbornene with PTz-liposome revealed the binding of 2-norbornene to tetrazine. Indium-111-labeled diethylenetriaminepentaacetic acid (111In-DTPA) was encapsulated inside PTz-liposome to evaluate the leakage of free 111In-DTPA from the liposomes quantitatively. After 24 h of adding 2-norbornene, the release percentage for PTz-liposome was significantly higher than that for the control liposome (without tetrazine structure). Furthermore, the membrane fluidity of the PTz-liposome was increased by adding 2-norbornene. These results suggested that the combination of dienophile and liposome containing a newly synthesized tetrazine derivative can be used as a controlled release DDS carrier. |
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| Keywords: | Tetrazine Amphiphilic material Bioorthogonal chemistry Liposome Drug delivery system Controlled release |
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