br Next we examined the applicability
Next, we examined the applicability of TAB-3-GSH for targeting tumor in vivo. A nude mouse implanted with subcutaneous xenografts of SKOV-3 cell line at the left posterior axillary was used as the animal model. After intraperitoneal (i.p.) injection of TAB-3-GSH (4 mM, 200 μL), fluorescence signal from the tumors sites were monitored for 1.5 h at every 10min interval. As recorded in Fig. 4, the fluorescence signal appeared in about 60 min and then continually increased for the next 30 min. At 90 min, the tumor area could be clearly located, in-dicating TAB-3-GSH has the ability for imaging tumor in vivo. As control, another nude mouse with tumor of SKOV-3 at right posterior axillary was pretreated by in-situ injection of DON before the injection
of TAB-3-GSH. The fluorescence enhancement was obviously inhibited. Thus, TAB-3-GSH could be used eﬀectively to image the GGT-over-expressing SKOV-3 tumor in vivo.
A water-soluble fluorescence probe for GGT, TAB-3-GSH, was de-veloped by functionalizing the triarylboron compound with multi GSH groups, which was covalently linked by amide bonds. A series of re-ference compounds, TAB-3-Cys-Gly, TAB-3-Cys, and TAB-3-GSH-Et, were also synthesized for a comparative study. TAB-3-GSH showed a slight fluorescence response for normal concentration of GGT, but greatly enhanced fluorescence intensity in presence of the abnormal concentration of GGT. Our observations showed that diﬀerent GGT concentrations can induce hydrolysis reaction at diﬀerent sites of the molecular structure of TAB-3-GSH: GGT can firstly hydrolyze the amide bond of GSH groups under normal GGT levels and then hydrolyze the amide linkage under abnormally high GGT levels. In cell imaging ex-periment, TAB-3-GSH could diﬀerentiate GGT-overexpressing ovarian cancer Fulvestrant (ICI 182,780) from normal cells because of its poor cell membrane per-meability, which improved after reaction with GGT. Moreover, TAB-3-GSH could also achieve accurate localization to tumor sites in mouse SKOV-3 tumor model. Thus, TAB-3-GSH is a promising probe for tar-geting GGT-overexpressing tumor in vivo and the proposed mechanism provides a novel strategy for designing fluorescent probes for detecting abnormal concentration of GGT.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influ-ence the work reported in this paper.
CRediT authorship contribution statement
Jun Liu: Investigation, Writing - original draft, Funding acquisition.
Shilu Zhang: Data curation. Bin Zhao: Methodology. Chengyi Shen:
Writing - review & editing. Xiaoming Zhang: Project administration.
Guoqiang Yang: Writing - review & editing.
We are grateful for the funding from the National Natural Science Foundation of China (Grant No. 81801768, 81871440), the Sichuan Science and Technology Department (Grant No. 2019YJ0385), the Scientific Research Project of Sichuan Provincial Department of Biosensors and Bioelectronics 142 (2019) 111497
Appendix A. Supplementary data
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Biomedicine & Pharmacotherapy
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A nuclear targeted Dox-aptamer loaded liposome delivery platform for the T circumvention of drug resistance in breast cancer
Xin Lia,b, Xiuhua Wua, Hongyu Yanga, Lin Lia, Ziqi Yea, Yuefeng Raoa,b,
a Department of Pharmacology, the First Aﬃliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
b Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Drug-resistant cancer therapy
The development of multidrug resistance (MDR) has become an increasingly serious problem in cancer therapy. The cell membrane overexpression of P-glycoprotein (P-gp), which can actively eﬄux various anticancer drugs in the cytoplasm from the cell, is a major mechanism of MDR. Nuclear-targeted nanoparticle drug delivery system, which enables intranuclear release of anticancer drugs, is expected to address this challenge. In this study, based on nucleolin’s active transport property to the nucleus and its aﬃnity with aptamer, we developed a nuclear-targeted delivery system to circumvention of drug resistance in breast cancer (MCF-7/Adr). Dox·HCl inserted in the aptamer AS1411 (Ap-Dox) was encapsulated in the aqueous interior of liposome (Lip(Ap-Dox)). In vitro studies showed that after the Lip(Ap-Dox) diﬀusing into MCF-7/Adr cells, Ap-Dox complex bound with nucleolin strongly and eventually entered the cell nuclei. By using this drug delivery system, Dox·HCl can ef-ficiently accumulated in the nuclei to eﬀectively kill the cancer cells.