Libang Zhang1,2,3, Dongjian Zhang1,2, Meng Gao1,2, Qiaomei Jin1,2, Cuihua Jiang1,2, Tianze Wu1,2,3, Yuanbo Feng4, Yicheng Ni4, Zhiqi Yin3, Jian Zhang5,6. 1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, People's Republic of China. 2. Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No.100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People's Republic of China. 3. Department of TCMs Pharmaceuticals, School of TCM & State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. 4. Theragnostic Laboratory, Campus Gasthuisberg, KU Leuven, 3000, Leuven, Belgium. 5. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, People's Republic of China. zjwonderful@hotmail.com. 6. Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No.100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People's Republic of China. zjwonderful@hotmail.com.
Abstract
PURPOSE: Visualization of tumor necrosis can determine tumor response to therapy. Our previous study showed that the rhein-based magnetic resonance imaging (MRI) contrast agent with alkane linker (GdL2) could clearly image tumor necrosis. However, its water solubility and cell safety needed to be improved. Herein, three rhein-based MRI agents with ether or lysine linkers were designed. PROCEDURES: Three rhein-based MRI agents were synthesized with a tetracarbon ether (GdP1), a hexacarbon ether (GdP2), and a lysine (GdP3) linker, respectively. Their octanol-water partition coefficients (log P) and cytotoxicity were determined. Necrosis avidity of the leading agent was explored on HepG2 cells and ischemia reperfusion-induced liver necrosis (IRLN) rats by MRI. The effect of visualization of tumor necrosis was tested on nude mice with W256 tumor treated by combretastatin-A4 phosphate (CA4P). DNA binding assays were applied to evaluate the possible necrosis-avidity mechanism of the leading agent. RESULTS: The log P of three agents (- 1.66 ± 0.09, - 1.74 ± 0.01, - 1.95 ± 0.01) decreased when compared with GdL2, indicating higher water solubility. GdP1 not only presented lower cytotoxicity and good necrotic affinity in vitro and in vivo, but also can be fast excreted by renal. According to MRI results of tumor, distinct visualization of tumor necrosis can be discernible from 3 to 4.5 h post-injection of GdP1. In DNA-binding assays, the fluorescence quenching constant KSV (1.00 × 104 M-1) and the ultraviolet binding constant Kb (1.11 × 104 M-1) suggested that GdP1 may bind to DNA through intercalation. CONCLUSION: GdP1 may serve as a potential candidate for early evaluation of tumor response to CA4P treatment.
PURPOSE: Visualization of tumor necrosis can determine tumor response to therapy. Our previous study showed that the rhein-based magnetic resonance imaging (MRI) contrast agent with alkane linker (GdL2) could clearly image tumor necrosis. However, its water solubility and cell safety needed to be improved. Herein, three rhein-based MRI agents with ether or lysine linkers were designed. PROCEDURES: Three rhein-based MRI agents were synthesized with a tetracarbon ether (GdP1), a hexacarbon ether (GdP2), and a lysine (GdP3) linker, respectively. Their octanol-water partition coefficients (log P) and cytotoxicity were determined. Necrosis avidity of the leading agent was explored on HepG2 cells and ischemia reperfusion-induced liver necrosis (IRLN) rats by MRI. The effect of visualization of tumor necrosis was tested on nude mice with W256 tumor treated by combretastatin-A4 phosphate (CA4P). DNA binding assays were applied to evaluate the possible necrosis-avidity mechanism of the leading agent. RESULTS: The log P of three agents (- 1.66 ± 0.09, - 1.74 ± 0.01, - 1.95 ± 0.01) decreased when compared with GdL2, indicating higher water solubility. GdP1 not only presented lower cytotoxicity and good necrotic affinity in vitro and in vivo, but also can be fast excreted by renal. According to MRI results of tumor, distinct visualization of tumor necrosis can be discernible from 3 to 4.5 h post-injection of GdP1. In DNA-binding assays, the fluorescence quenching constant KSV (1.00 × 104 M-1) and the ultraviolet binding constant Kb (1.11 × 104 M-1) suggested that GdP1 may bind to DNA through intercalation. CONCLUSION:GdP1 may serve as a potential candidate for early evaluation of tumor response to CA4P treatment.
Entities:
Keywords:
Combretastatin-A4 phosphate; Effect of linkers; Magnetic resonance imaging; Rhein; Tumor necrosis
Authors: Thomas Nielsen; Lise Bentzen; Michael Pedersen; Trine Tramm; Paul F J W Rijken; Johan Bussink; Michael R Horsman; Leif Østergaard Journal: Clin Cancer Res Date: 2012-10-15 Impact factor: 12.531
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Karol Jaroch; Maciej Karolak; Przemysław Górski; Alina Jaroch; Adrian Krajewski; Aleksandra Ilnicka; Anna Sloderbach; Tomasz Stefański; Stanisław Sobiak Journal: Pharmacol Rep Date: 2016-08-24 Impact factor: 3.024
Authors: Ash A Alizadeh; Victoria Aranda; Alberto Bardelli; Cedric Blanpain; Christoph Bock; Christine Borowski; Carlos Caldas; Andrea Califano; Michael Doherty; Markus Elsner; Manel Esteller; Rebecca Fitzgerald; Jan O Korbel; Peter Lichter; Christopher E Mason; Nicholas Navin; Dana Pe'er; Kornelia Polyak; Charles W M Roberts; Lillian Siu; Alexandra Snyder; Hannah Stower; Charles Swanton; Roel G W Verhaak; Jean C Zenklusen; Johannes Zuber; Jessica Zucman-Rossi Journal: Nat Med Date: 2015-08 Impact factor: 53.440
Authors: Freddie Bray; Jacques Ferlay; Isabelle Soerjomataram; Rebecca L Siegel; Lindsey A Torre; Ahmedin Jemal Journal: CA Cancer J Clin Date: 2018-09-12 Impact factor: 508.702
Authors: Susan M Galbraith; Ross J Maxwell; Martin A Lodge; Gillian M Tozer; John Wilson; N Jane Taylor; J James Stirling; Luiza Sena; Anwar R Padhani; Gordon J S Rustin Journal: J Clin Oncol Date: 2003-06-13 Impact factor: 44.544
Authors: Marcus C M Stroet; Erik de Blois; Joost Haeck; Yann Seimbille; Laura Mezzanotte; Marion de Jong; Clemens W G M Löwik; Kranthi M Panth Journal: Contrast Media Mol Imaging Date: 2021-12-13 Impact factor: 3.161