MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Hui Liu,Yuxiang Han,Jiyuan Li,Ming Qin,Qunfeng Fu,Chunhong Wang,Zhibo Liu
Amino acids derivative are well established molecular probes for diagnosis of a variety of cancer using positron emission tomography (PET). Recently, boramino acid (BAAs) was found as a prospective molecular platform for developing PET tracer. The objective of this study was to develop a 18F-labeled alanine derivative through displacing its carboxylate by trifluoroborate as a selective ASCT2 marker for cancer imaging. 18F-Ala-BF3 was first evaluated in healthy FVB/N mice in vivo, exhibiting rapid renal clearance with almost negligible uptake in stomach (1.53 ± 0.31%ID/g). Notable uptake was observed in thyroid (3.71 ± 0.49%ID/g, 40 min post injection), of which the uptake was significantly inhibited by co-injection with natural L-alanine. In addition, we further established 18F-Ala-BF3 on a human gastric cancer cell (BGC-823) xenografts bearing mouse model. Dynamic PET-CT scan revealed the optimal time window for tumor imaging, it was between 40 and 60 min post injection, when the BGC-823 xenografts uptake was 5.49 ± 1.47%ID/g (n = 4), and the tumor-to-stomach, tumor-to-blood, tumor-to-muscle, and tumor-to-brain ratios were 3.27 ± 1.53, 3.80 ± 1.48, 3.47 ± 1.48, and 6.20 ± 1.47, respectively.
研究领域:
医学影像学
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肿瘤学
·
分子生物学
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DOI
PubMed
高影响因子
BIOLOGICAL TRACE ELEMENT RESEARCH
·
2023
·
IF 3.9
Cui Jinling,Li Jingsi,Zhao Shuang,Fan Lihong,Yin Shutao,Zhao Chong,Hu Hongbo
Drug combination is considered to be an effective approach to improve the efficacy of cancer therapy and chemoprevention. Selenite, a representative of inorganic form of selenium, and butyrate, a major short-chain fatty acid, are two well-documented colon cancer dietary chemopreventive agents with distinct molecular mechanisms. We hypothesized that combination of selenite and butyrate might produce improved outcome against colon cancer. This hypothesis was tested using both HCT116 human colon cancer cells and its xenograft mouse model in the present study. The in vitro study showed a synergistically inhibitory effect on HCT116 colon cancer cells but not on NCM460 normal human colon mucosal epithelial cells. Consistent with the in vitro study, results of the xenograft mouse model further demonstrated that combination of selenite and butyrate led to improved efficacy in comparison with each agent alone. Mechanistically, the induction of alanine-serine-cysteine transporter 2 (ASCT2) by selenite repressed its inhibitory effect on colon cancer cells, which was reversed by its co-treatment with butyrate. The findings of the present study denote the likely potential for developing selenite/butyrate combination remedy to combat against colon cancer.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Nanomaterials
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2020
·
IF 1.98
Yi-Zhi Zhu,Di Xu,Zhen Liu,Tian Tian,Fei Deng,Wen-Juan Tang,Yang Wu,Wei Zhang,Jin-Hai Tang
Triple-negative breast cancer (TNBC) is a highly malignant tumor. At present, there are still no targeted drugs for TNBC. Clinical chemotherapeutic drugs, such as doxorubicin (DOX), have the characteristic of nontargeted distribution in treatment of TNBC, causing severe side effects. Therefore, new target treatment strategies for TNBC are of urgent need. It was speculated that glutamine could be a potential target because it is in high demand by TNBC. In this study, we found that the transporter for glutamine, ASCT2 (solute carrier family 1 member 5 (SLC1A5)), is highly expressed in TNBC by analysis of data from The Cancer Genome Atlas (TCGA) and experiments in vitro. Based on this, glutamine was grafted onto a polymeric drug carrier in order to develop a tumor-targeting drug delivery system for treatment of TNBC. Firstly, pH-responsive glutamine-PEG5000-b-PAE10000 (Gln-PEG-b-PAE) copolymers were synthesized using Fmoc-PEG5000-b-PAE10000 (Fmoc-PEG-b-PAE) copolymers. Then, Gln-PEG-b[email protected] micelles were prepared by loading DOX to Gln-PEG-b-PAE copolymer using a solvent casting technology. In vitro, Gln-PEG-b[email protected] micelles exhibited pH-dependent micellization-decellularization behavior; namely, they can rapidly release DOX in acidic environment of pH 6.0 but release very slowly in physiological condition. Moreover, glutamine competition experiment showed that Gln-PEG-b[email protected] micelles had the ability to target MDA-MB-231 cells. Compared to free DOX, Gln-PEG-b[email protected] micelles had significantly greater cytotoxic effect and antiproliferative activity against MDA-MB-231 cells. In vivo, compared to free DOX and mPEG-b[email protected] micelles, Gln-PEG-b[email protected] micelles significantly inhibited tumor growth in tumor-bearing mice. Therefore, Gln-PEG-b[email protected] micelles, as a tumor-targeting drug delivery system, may provide a new method for the treatment of TNBC.
研究领域:
药学
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聚合物化学
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肿瘤学
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药物递送系统
✓ 已验证
产品关联
DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Jiamin Wu,Zhi Li,Zeping Yang,Ling Guo,Ye Zhang,Huihui Deng,Cuifeng Wang,Min Feng
It is not efficient enough using the current approaches for tumor-selective drug delivery based on the EPR effect and ligand–receptor interactions, and they have largely failed to translate into the clinic. Therefore, it is urgent to explore an enhanced strategy for effective delivery of anticancer agents. Clinically, many cancers require large amounts of glutamine for their continued growth and survival, resulting in circulating glutamine extraction by the tumor being much greater than that for any organs, behaving as a “glutamine trap”. In the present study, we sought to elucidate whether the glutamine-trap effect could be exploited to deliver therapeutic agents to selectively kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized branched polyethylenimine (GPI), was constructed as the carrier to deliver anti-CD47 siRNA for the blockage of CD47 “don’t eat me” signals on cancer cells. The GPI/siRNA glutamine-rich polyplexes exhibited remarkably high levels of cellular uptake by glutamine-dependent lung cancer cells, wild-type A549 cells (A549WT), and its cisplatin-resistant cells (A549DDP), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549WT and A549DDP but with almost no expression in normal human lung fibroblasts cells. Inhibition of ASCT2 significantly prevented the internalization of GPI polyplexes. These findings raised the intriguing possibility that the glutamine-rich GPI polyplexes utilize the ASCT2 pathway to selectively facilitate their cellular uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently both in vitro and in vivo to downregulate the intratumoral mRNA and protein expression levels of CD47. CD47 functions as a “don’t eat me” signal and binds to the immunoreceptor SIRPα inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes achieved significant antitumor activities both on A549WT and A549DDP tumor-bearing nude mice. Notably, it had no adverse effect on CD47-expressing red blood cells and platelets, likely because of selective delivery. Therefore, the glutamine-rich carrier GPI driven by the glutamine-trap effect provides a promising new strategy for designing anticancer drug delivery systems.
研究领域:
肿瘤学
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药学
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分子生物学
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癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2024
·
IF 10.7
Wei Li,Qingwen Zeng,Bing Wang,Chao Lv,Haoan He,Xi Yang,Bin Cheng,Xiaoan Tao
Although oxidative stress is closely associated with tumor invasion and metastasis, its’ exact role and mechanism in the initial stage of oral cancer remain ambiguous. Glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) participates in glutathione synthesis to resolve oxidative stress. Currently, we firstly found that ASCT2 deletion caused oxidative stress in oral mucosa and promoted oral carcinogenesis induced by 4-Nitroquinoline-1-oxide (4-NQO) using transgenic mice of ASCT2 knockout in oral epithelium. Subsequently, we identified an upregulated gene Thbs1 linked to macrophage infiltration by mRNA sequencing and immunohistochemistry. Importantly, multiplex immunohistochemistry showed M1-like tumor-associated macrophages (TAMs) were enriched in cancerous area. Mechanically, targeted ASCT2 effectively curbed glutamine uptake and caused intracellular reactive oxygen species (ROS) accumulation, which upregulated Thbs1 in oral keratinocytes and then activated p38, Akt and SAPK/JNK signaling to polarize M1-like TAMs via exosome-transferred pathway. Moreover, we demonstrated M1-like TAMs promoted malignant progression of oral squamous cell carcinoma (OSCC) both in vitro and in vivo by a DOK transformed cell line induced by 4-NQO. All these results establish that oxidative stress triggered by ASCT2 deletion promotes oral carcinogenesis through Thbs1-mediated M1 polarization, and indicate that restore redox homeostasis is a new approach to prevent malignant progression of oral potentially malignant disorders.
研究领域:
癌症生物学
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免疫学
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细胞生物学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-20
·
IF 10.2
Ai Chen,Sun Xiao,Xiao Shan,Guo Lu,Shang Mengmeng,Shi Dandan,Meng Dong,Zhao Yading,Wang Xiaoxuan,Li Jie
Despite rapid advances in metabolic therapies over the past decade, their efficacy in melanoma has been modest, largely due to the interaction between cancer-associated fibroblasts (CAFs) and cancer cells to promote cancer growth. Altering the tumor microenvironment (TME) is challenging and elusive. CAFs is critical for glutamine deprivation survival in melanoma. In this research, we assembled a CAFs-targeted, controlled-release nanodroplets for the combined delivery of the amino acid transporter ASCT2 (SLC1A5) inhibitor V9302 and GLULsiRNA (siGLUL). The application of ultrasound-targeted microbubble disruption (UTMD) allows for rapid release of V9302 and siGLUL, jointly breaking the glutamine metabolism interaction between CAFs and cancer cells on one hand, on the other hand, blocking activated CAFs and reducing the expression of extracellular matrix (ECM) to facilitate drug penetration. In addition, ultrasound stimulation made siGLUL more accessible to tumor cells and CAFs, downregulating GLUL expression in both cell types. FH-V9302-siGLUL-NDs also serve as contrast-enhanced ultrasound imaging agents for tumor imaging. Our study developed and reported FH-NDs as nanocarriers for V9302 and siGLUL, demonstrating that FH-V9302-siGLUL-NDs have potential bright future applications for integrated diagnostic therapy.
Graphical Abstract
研究领域:
肿瘤学
·
药理学
·
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）