JOURNAL OF CHROMATOGRAPHY A
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2025
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IF 4
Tao Huang,Chunsu Liang,Jilun Li,Xiaomei Ling
High performance capillary electrophoresis (HPCE) has been widely applied in the analysis of amino acids (AAs), but no studies on the HPCE analysis of dissociated states of AAs have been reported. Here, twenty proteingenic AAs were analyzed by the newly-developed universal interface-induced current detector (IICRD). Two or three current signal peaks were observed in current electrophoretograms (CR-EGs), while only one peak with low sensitivity can be obtained by DAD. The current signal peaks of AAs were accurately identified by adding charge-neutral marker, comparing current signal peaks at different pH conditions, also calculating by p K a . The qualitative analysis indicated that the three current signal peaks of basic AAs were monovalent cations ([AA + ]), charge-neutral forms ([AA ± ]), and monovalent anions ([AA - ]) in order. Similarly, acidic AAs can be detected in three forms as [AA ± ], [AA - ] and [AA 2- ], while neutral AAs can be detected as [AA ± ] and [AA - ]. Quantitative analysis showed that HPCE-IICRD can enhance the sensitivity of AAs to 40 μmol/L in LOD, with a linear range from 10 –6 mol/L to 10 –2 mol/L. Furthermore, interactions between different dissociated states of twenty AAs and l -type amino acid transporter (LAT1) were studied by combined application of NICCE method for the first time. The binding kinetic parameters and mole number of LAT1 on cell membranes can also be obtained. Besides, competitive binding experiments proved that JPH203 (LAT1-specific inhibitor) and leucine shared the same binding site. HPCE-IICRD provides a new method to reveal the interaction between different dissociated forms of AAs or other biomolecules and essential receptors.
研究领域:
生物化学
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分析化学
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产品关联
DOI
PubMed
高影响因子
Cancers
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2022
·Vol. 14
·期 10
·2551
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IF 6.575
Qingwen Xu,Yuxi Liu,Wen Sun,Tiantian Song,Xintong Jiang,Kui Zeng,Su Zeng,Lu Chen,Lushan Yu
Simple SummaryThe transformation and mechanism of methionine metabolism of renal cell carcinoma (RCC) under a hypoxic microenvironment is not well understood as yet. This study illustrated that the reprogramming of methionine metabolism and the subsequent glutathione (GSH) synthesis were mediated by amino acid transporter 1 (LAT1). Correspondingly, we proposed a combination strategy of LAT1 inhibitor JPH203 and oxaliplatin, which presented an enhanced therapeutic efficacy for RCC both in vivo and in vitro.AbstractHypoxic microenvironment and metabolic dysregulation of tumor impairs the therapeutic efficacy of chemotherapeutic drugs, resulting in drug resistance and tumor metastasis, which has always been a challenge for the treatment of solid tumors, including renal cell carcinoma (RCC). Herein, starting from the evaluation of methionine metabolism in RCC cells, we demonstrated that the increased methionine accumulation in RCC cells was mediated by L-type amino acid transporter 1 (LAT1) under hypoxia. Glutathione (GSH), as a methionine metabolite, would attenuate the therapeutic efficacy of oxaliplatin through chemical chelation. Reducing methionine uptake by LAT1 inhibitor JPH203 significantly enhanced the sensitivity of RCC cells to oxaliplatin by reducing GSH production in vitro and in vivo. Therefore, we proposed an effective and stable therapeutic strategy based on the combination of oxaliplatin and LAT1 inhibitor, which is expected to solve the resistance of RCC to platinum-based drugs under hypoxia to a certain extent, providing a meaningful insight into the development of new therapeutic strategies and RCC treatmentKeywords:renal cell carcinoma;hypoxia;methionine metabolism;LAT1;drug combination
研究领域:
肿瘤学
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癌症生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
Nano Research
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2023
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IF 9.9
Zhang Yufei,Cheng Qian,Xue Yuhao,Yao Kai,Syeda Madiha Zahra,Xu Jian,Wu Jianheng,Wang Zhenjie,Tang Longguang,Mu Qingchun
Glioma is the most common primary craniocerebral tumor caused by the cancerous growth of glial cells in the brain and spinal cord. Currently, standard treatment is the surgical resection followed by concurrent radiation and chemotherapy. However, the blood-brain barrier (BBB) prevents most antitumor drugs from entering the brain and reduces their efficacy, especially in low-grade glioma. Since L-type amino acid transporter 1 (LAT1) is highly expressed in glioma cells and mediates drug transport across the BBB, it is a promising target for drug delivery and treatment of glioma. Temozolomide (TMZ) is the first-line treatment for glioma, however, patients often exhibit drug resistance at advanced stage. A multikinase inhibitor and inducer of ferroptosis, sorafenib can improve the therapeutic effects of TMZ. Therefore, to optimize the glioma treatment and cross the BBB, we designed LAT1-targeting nanoparticles co-loaded with TMZ and sorafenib. Our results from both in vitro and in vivo studies confirmed that LAT1-targeting nanoparticles significantly increased the cellular uptake, cytotoxicity, accumulation at tumor site, and the anti-tumor efficacy compared to the non-target nanoparticles. Therefore, LAT1 can be used as a potential target for brain-targeted drug delivery, and sorafenib-induced ferroptosis can aid the anti-glioma efficacy of TMZ.
研究领域:
肿瘤学
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神经科学
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药学
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纳米技术
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产品关联
DOI
高影响因子
Nanomedicine-Nanotechnology Biology and Medicine
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2016
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IF 5.671
Lin Li,Xingsheng Di,Mingrui Wu,Zhisu Sun,Lu Zhong,Yongjun Wang,Qiang Fu,Qiming Kan,Jin Sun,Zhonggui He
Designing active targeting nanocarriers with increased cellular accumulation of chemotherapeutic agents is a promising strategy in cancer therapy. Herein, we report a novel active targeting strategy based on the large amino acid transporter 1 (LAT1) overexpressed in a variety of cancers. Glutamate was conjugated to polyoxyethylene stearate as a targeting ligand to achieve LAT1-targeting PLGA nanoparticles . The targeting efficiency of nanoparticles was investigated in HeLa and MCF-7 cells. Significant increase in cellular uptake and cytotoxicity was observed in LAT1-targeting nanoparticles compared to the unmodified ones. More interestingly, the internalized LAT1 together with targeting nanoparticles could recycle back to the cell membrane within 3 h, guaranteeing sufficient transporters on cell membrane for continuous cellular uptake. The LAT1 targeting nanoparticles exhibited better tumor accumulation and antitumor effects. These results suggested that the overexpressed LAT1 on cancer cells holds a great potential to be a high-efficiency target for the rational design of active-targeting nanosystems .
研究领域:
药学
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肿瘤学
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生物医学工程
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DOI
PubMed
高影响因子
Drug Design Development and Therapy
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2024
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IF 4.7
Shaoguang Li,Zhan Lin,Haobo Chen,Qiu Luo,Shengnan Han,Kunlong Huang,Ruichan Chen,Yuying Zhan,Bing Chen,Hong Yao
Background The preclinical diagnosis of tumors is of great significance to cancer treatment. Near-infrared fluorescence imaging technology is promising for the in-situ detection of tumors with high sensitivity.Methods Here, a fluorescent probe was synthesized on the basis of Au nanoclusters with near-infrared light emission and applied to fluorescent cancer cell labeling. Near-infrared methionine-N-Hydroxy succinimide Au nanoclusters (Met-NHs-AuNCs) were prepared successfully by one-pot synthesis using Au nanoclusters, methionine, and N-Hydroxy succinimide as frameworks, reductants, and stabilizers, respectively. The specific fluorescence imaging of tumor cells or tissues by fluorescent probe was studied on the basis of SYBYL Surflex-DOCK simulation model of LAT1 active site of overexpressed receptor on cancer cell surface. The results showed that Met-NHs-AuNCs interacted with the surface of LAT1, and C_Score scored the conformation of the probe and LAT1 as five.Results Characterization and in vitro experiments were conducted to explore the Met-NHs-AuNCs targeted uptake of cancer cells. The prepared near-infrared fluorescent probe (Met-NHs-AuNCs) can specifically recognize the overexpression of L-type amino acid transporter 1 (LAT1) in cancer cells so that it can show red fluorescence in cancer cells. Meanwhile, normal cells (H9c2) have no fluorescence.Conclusion The fluorescent probe demonstrates the power of targeting and imaging cancer cells.
研究领域:
生物医学工程
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肿瘤学
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分子影像学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2019
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IF 7.901
Zhenjie Wang,Dongxu Chi,Xingchen Wu,Yingli Wang,Xinxin Lin,Zhaochu Xu,Hongzhuo Liu,Jin Sun,Zhonggui He,Yongjun Wang
As the demand for nutrients in malignant proliferation of tumors increases, the L-type amino acid transporter 1(LAT1) and amino acid transporter B 0,+ (ATB 0,+ ) of tumor cells are more highly expressed than normal cells which can be used as new targets for active targeting of cancer. However, drug delivery systems often require multi-target design to achieve simultaneous targeting of different receptors or transporters due to the heterogeneity of the tumor. Here we utilized triethylamine-sucrose octasulfate gradient to actively encapsulate irinotecan into the introliposomal aqueous phase. Targeted ability was achieved through inserting different amino acids modified polyethylene glycol monostearate into the liposomes , and found that glutamate-liposomes can be targeted to LAT1, lysine-liposomes can be targeted to ATB 0,+ , and inspiringly, tyrosine-liposomes can be simultaneously targeted to LAT1 and ATB 0,+ . The tyrosine-modified liposomes showed the highest cellular uptake in BxPC-3 and MCF-7 cells which were highly expressed both LAT1 and ATB 0,+ . Moreover, we validated their targeting capabilities and elucidated the transport mechanism of LAT1 and ATB 0,+ -mediated endocytosis. The tumor inhibition rate of tyrosine-modified liposomes greatly increased from 39% to 87% compared with commercially available liposomes loaded CPT-11(Onivyde®). Overall, it showed a good application prospect for efficient tumor therapy and industrial production.
研究领域:
药学
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肿瘤学
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药物递送
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DOI
PubMed
高影响因子
Science China-Chemistry
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2023
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IF 9.6
Liu Xun,Si Wenting,Zhao Ziyin,Liu Ningyu,Yang Qiang,Zhou Renxiang,Zhu Rongying,Duan Shanzhou,Chen Yongbing,Yin Lichen
Intracellular protein therapeutics holds great potentials for the treatment of glioblastoma, which however, is greatly challenged by the unmet demands to concomitantly penetrate the blood-brain barrier (BBB) and glioblastoma cell membrane barrier with high efficiency and selectivity. Herein, a unique pro-protein platform was developed via facile green synthesis, which allowed efficient and selective delivery into glioblastoma cells in a carrier-free manner. Pro-proteins were engineered via reversible modification of native proteins in the aqueous buffer with 3,4-dihydroxy-phenylalanine, the substrate of L -type amino acid transporter (LAT1), bridged with a phenylboronic acid-containing linker. By harnessing the LAT1-mediated direct transport mechanism, the optimized pro-protein, named protein-M2-D, can efficiently penetrate BBB after i.v. injection, and subsequently enable selective and endocytosis-free delivery of various proteins including enzymes, toxins, and antibodies into glioblastoma cells, wherein intracellular H 2 O 2 triggered traceless restoration of the native protein structure. Systemic administration of saporin-M2-D provoked potent anti-tumor efficacy against orthotopic U87 glioblastoma in mice, without inducing systemic toxicity. Such a facile, versatile, and robust platform renders a promising paradigm for cytosolic protein delivery and glioblastoma treatment.
研究领域:
神经科学
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癌症生物学
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药学
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分子生物学
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产品关联
DOI
高影响因子
FREE RADICAL BIOLOGY AND MEDICINE
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2025
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IF 8.2
Xiao He,Zhongmin Wang,Huayang Bai,Yaqin Tang,Daimeng Feng,Shuyu Zhang,Robert J. Lee,Jing Xie,Yansun Sun
Breast cancer remains a major global health challenge, with triple-negative breast cancer (TNBC) posing a particular therapeutic dilemma due to its lack of targetable receptors and reliance on chemotherapy, which is often thwarted by drug resistance. To overcome these limitations, we developed a novel metal-polyphenol nano-platform (DLF@NPs) via a one-pot coordination assembly of L-dopa (L-DA), doxorubicin (DOX), and ferrous ions (Fe 2+ ). This GSH/pH-dual-responsive nanoparticle exploits the overexpression of L-type amino acid transporter 1 (LAT1) on breast cancer cells for targeted delivery and tumor-specific enrichment, effectively addressing the off-target toxicity and resistance associated with free DOX. Upon internalization into the acidic and high-GSH tumor microenvironment, DLF@NPs rapidly disassemble, releasing their payload. The liberated DOX not only exerts its apoptotic effect but also activates NADPH oxidases (NOXs) to elevate intracellular H 2 O 2 levels. This endogenous H 2 O 2 supply fuels a Fenton reaction catalyzed by the co-released Fe 2+ , generating highly toxic hydroxyl radicals. Furthermore, L-DA reduces the resultant Fe 3+ back to Fe 2+ , establishing a catalytic cycle that robustly amplifies reactive oxygen species (ROS). The resultant ROS burst synergizes with DOX by inducing severe mitochondrial damage, leading to potentiated apoptosis. In summary, this work proposes a novel targeted nanoplatform that utilizes the synergy between chemodynamic therapy and chemotherapy to provide a promising strategy for combating drug-resistant breast cancer.
研究领域:
纳米医学
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癌症治疗
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乳腺癌研究
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药物递送
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活性氧（ROS）
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化学动力学治疗
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靶向治疗
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2021
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IF 13.273
Xinyu Jiang,Qing Yao,Xing Xia,Yingying Tang,Meng Sun,Yingtao Li,Hailun Zheng,Aimin Cai,Hailin Zhang,Vadivel Ganapathy,Ruijie Chen,Longfa Kou
Psoriasis is a chronic inflammatory skin disease with dysregulation of the immune system, which usually manifests as erythematous scleroma with hyperplasia of the epidermis. Although the pathogenesis remains unclear, oxidative stress and inflammation are inextricably linked during the development of psoriasis. Therefore, scavenging of ROS and suppression of inflammation may be a rational and effective strategy to ameliorate psoriasis and delay its further development. Here, a “Tanghulu”-like nanoplatform (BJN) is developed using the endogenous antioxidant bilirubin and a specific inhibitor (JPH203) of LAT1, an amino acid transporter involved in the activation of mTOR, for treatment of psoriasis by scavenging ROS and interfering with mTOR signaling, consequently blocking Th17 and IL-17 release. The nanoparticles show increased uptake in inflamed keratinocytes and display an efficient ROS scavenging capability. In an in vivo psoriasis model, BJN effectively permeate into the inflamed skin and be retained there, thereby reversing the psoriasis-specific changes in the imiquimod-induced mice as evident from suppression of keratinocyte hyperplasia and decrease in immune cell infiltration. This study shows that BJN can exert a superior anti-psoriasis effect by scavenging ROS, blocking the LAT1-mTOR pathway, inactivating immune reaction, restricting Th17 differentiation, and decreasing IL-17A secretion, offering a promising strategy for psoriasis treatment.
研究领域:
药学
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免疫学
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皮肤病学
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纳米技术
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分子生物学
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DOI
高影响因子
Biomaterials Science
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2025
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IF 5.7
Yanting Li,Mengdan Ning,Haoping Long,Jiayi Zuo,Jinqiu Liang,Ting Yuan,Feng Cao,Yong Yin,Feng Jiang
To overcome therapy resistance driven by breast cancer stem cells (BCSCs) and systemic toxicity of conventional chemotherapy, we engineered a multistimuli-responsive nanoprodrug (DT/PAC@AI NPs) implementing a "chemodifferentiation-cancer stem cells inhibition" strategy. This system co-delivers irinotecan (IRI), all-trans retinoic acid (ATRA), and CPUL119 via: (1) a hypoxia-responsive prodrug (PAC: PEG₂ₖ-Azo-CPUL119), and (2) a pH/esterase-responsive conjugate (AI: ATRA-IRI). The targeted NPs (90-130 nm), modified with DSPE-PEG₂ₖ-Try for LAT1mediated uptake, demonstrated tumor microenvironment-triggered release: rapid PAC release under hypoxia and enhanced AI release at pH 5.0/esterase. In vitro, DT/PAC@AI NPs showed 20% higher cellular uptake and potent cytotoxicity against MDA-MB-231 cells (IC₅₀ = 4.77 ± 0.32 µM vs. free drugs: IRI 23.17, CPUL119 9.27, ATRA >50 µM), inducing 3.7-fold more apoptosis (32.6% vs. 8.7%). Critically, they reduced CD44⁺/CD24⁻ BCSCs by 13.7% and inhibited tumor sphere formation by 87.6%. In vivo, they achieved optimal tumor suppression and BCSC elimination in xenografts with negligible systemic toxicity. This nanoprodrug platform offers straightforward synthesis, high drug loading, and potent dual-action efficacy against bulk tumor cells and BCSCs, presenting a promising advanced breast cancer therapy.
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2020
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IF 4.845
Zhenjie Wang,Xinxin Lin,Dongxu Chi,Zhaochu Xu,Guimei Lin,Hongzhuo Liu,Jin Sun,Zhonggui He,Yongjun Wang
Along with the malignant proliferation of tumor requiring nutrients, the expression of L-type amino acid transporter 1(LAT1) and amino acid transporter B 0,+ (ATB 0,+ ) in cancer cells is up-regulated that can be used as new targets for active targeting of tumor. However, since normal cells also express amino acid transporters in small amounts, traditional ligand-exposure drug delivery systems are potentially toxic to the body. Therefore, we designed a smart-response drug delivery system that buries the tyrosine ligand in PEG hydration layer at normal tissues and exposes the ligand by cleaving the pH-sensitive bond of PEG at the tumor site. Irinotecan (CPT-11) is actively loaded into the inner aqueous phase of liposomes via a copper ion gradient mechanism which has high encapsulation efficiency and stable drug release profile. Smart-response liposomes showed the strongest cytotoxicity and the maximum cellular uptake in vitro , the largest amount of tumor site accumulation and the best antitumor effect in vivo , compared with non-targeted liposomes and non-sensitive liposomes. It is worth noting that smart-response liposomes not only achieved enhanced antitumor effect but also attenuated side effects compared to ligand-exposure liposomes. This provides a smart responsive drug delivery system for precise treatment and shows a good application prospect.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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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）