MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Jian Cui,Zhiwei Wen,Huajie Huang,Shuilin Qin,Yanjie Luo,Wei Zhang,Wei Wu
The disadvantage of a traditional dosage regimen is the inability to deliver a sufficient drug concentration to the lesion site, which can result in adverse side effects due to nonspecific drug delivery. Actively targeting hepatic cells is a promising therapeutic strategy for liver disease. In this study, l-carnitine and a targeting peptide derived from the hepatitis B virus large envelope protein were used to modify liposomes for drug delivery to the liver through the sodium taurocholate cotransporting polypeptide (NTCP) and the organic cation/carnitine transporter 2 (OCTN2) receptors. Silybin was selected as the model drug. The solubility of silybin can reach 0.3 mg/mL after encapsulation in liposomes. The NTCP-specific and OCTN2-accelerated Myrcludex B and l-carnitine dual-modified liposomes were validated in vitro. The uptake of coumarin-6 in dual ligand-modified liposomes by hepatocytes was up to 2.36 μg/mg compared with unmodified liposomes (1.05 μg/mg). The pharmacokinetics and targeting abilities of various liposome formulations were evaluated in Kunming mice. Targeted liposomes increased the concentration of silybin and prolonged the drug’s retention time in the liver. The area under the liver’s pharmacokinetic curve of targeted liposomes was twice that of silybin injection, suggesting the promising application potential of silybin-loaded hepatotropic nanovesicles.
研究领域:
药理学
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药物递送系统
·
肝脏疾病治疗
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DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2019
·Vol. 47
·期 6
·582-591
·
IF 3.354
Mengru Bai,Qingquan Zeng,Yingchun Chen,Mingyang Chen,Ping Li,Zhiyuan Ma,Dongli Sun,Hui Zhou,Caihong Zheng,Su Zeng,Huidi Jiang
l-Carnitine (l-Car) plays a crucial role in fatty acid β-oxidation. However, the plasma l-Car concentration in women markedly declines during pregnancy, but the underlying mechanism and its consequences on maternal hepatic β-oxidation have not yet been clarified. Our results showed that the plasma l-Car level in mice at gestation day (GD) 18 was significantly lower than that in nonpregnant mice, and the mean fetal-to-maternal plasma l-Car ratio in GD 18 mice was 3.0. Carnitine/organic cation transporter 2 (OCTN2) was highly expressed in mouse and human placenta and upregulated as gestation proceeds in human placenta, whereas expressions of carnitine transporter (CT) 1, CT2, and amino acid transporter B0,+ were extremely low. Further study revealed that renal peroxisome proliferator–activated receptor α (PPARα) and OCTN2 were downregulated and the renal l-Car level was reduced, whereas the urinary excretion of l-Car was lower in late pregnant mice than in nonpregnant mice. Meanwhile, progesterone (pregnancy-related hormone) downregulated the expression of renal OCTN2 via PPARα-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of l-Car and β-hydroxybutyrate (an indicator of mitochondrial β-oxidation), and mRNA levels of several enzymes involved in fatty acid β-oxidation in GD 18 mice were higher than that in nonpregnant mice. In conclusion, OCTN2 mediated l-Car transfer across the placenta played a major role in maternal plasma l-Car reduction during pregnancy, which did not subsequently result in maternal hepatic fatty acid β-oxidation decrease.
研究领域:
生理学
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药理学
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内分泌学
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生殖生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2024
·Vol. 22
·期 1
·1-19
·
IF 10.6
Tang Bo,Wang Qiuxiang,Zhang Guowei,Zhang Aiwen,Zhu Lu,Zhao Rongrong,Gu Hongwei,Meng Jie,Zhang Junfang,Fang Guihua
Traditional eye drops are administered via topical instillation. However, frequent dosing is needed due to their relatively rapid precorneal removal and low ocular bioavailability. To address these issues, stearoyl L- carnitine-modified nanoemulsions (SC-NEs) were fabricated. The physicochemical properties of SC-NEs in terms of size, morphology, zeta potential, encapsulation efficiency, and in vitro drug release behavior were characterized. The cellular uptake and mechanisms of SC-NEs were comprehensively studied in human corneal epithelial cells and the stearoyl L- carnitine ratio in SC-NEs was optimized. The optimized SC-NEs could target the novel organic cation/carnitine transporter 2 (OCTN2) and amino acid transporter B (0 +) (ATB 0,+ ) on the corneal epithelium, which led to superior corneal permeation, ocular surface retention ability, ocular bioavailability. Furthermore, SC-NEs showed excellent in vivo anti-inflammatory efficacy in a rabbit model of endotoxin-induced uveitis. The ocular safety test indicated that the SC-NEs were biocompatible. In general, the current study demonstrated that OCTN2 and ATB 0,+ -targeted nanoemulsions were promising ophthalmologic drug delivery systems that can improve ocular drug bioavailability and boost the therapeutic effects of drugs for eye diseases. Graphical Abstract
研究领域:
药剂学
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眼科学
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药物递送系统
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纳米技术
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DOI
PubMed
高影响因子
TOXICOLOGY LETTERS
·
2019
·
IF 3.499
Ting Jiang,Yingqiong Zhang,Mengru Bai,Ping Li,Wei Wang,Mingyang Chen,Zhiyuan Ma,Su Zeng,Hui Zhou,Huidi Jiang
Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic β-hydroxybutyrate level (indicator of fatty acid β-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 μM of IC 50 ), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.
研究领域:
药理学
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肝病学
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分子生物学
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DOI
PubMed
高影响因子
DRUG DELIVERY
·
2020
·
IF 4.902
Longfa Kou,Rui Sun,Shuyi Xiao,Xiao Cui,Jin Sun,Vadivel Ganapathy,Qing Yao,Ruijie Chen
Targeted nanocarriers have shown great promise in drug delivery because of optimized drug behavior and improved therapeutic efficacy. How to improve the targeting efficiency of nanocarriers for the maximum possible drug delivery is a critical issue. Here we developed L-carnitine-conjugated nanoparticles targeting the carnitine transporter OCTN2 on enterocytes for improved oral absorption. As a variable, we introduced various lengths of the polyethylene glycol linker (0, 500, 1000, and 2000) between the nanoparticle surface and the ligand (CNP, C5NP, C10NP and C20NP) to improve the ligand flexibility, and consequently for more efficient interaction with the transporter, to enhance the oral delivery of the cargo load into cells. An increased absorption was observed in cellular uptake in vitro and in intestinal perfusion assay in situ when the polyethylene glycol was introduced to link L-carnitine to the nanoparticles; the highest absorption was achieved with C10NP. In contrast, the linker decreased the absorption efficiency in vivo. As the presence or absence of the mucus layer was the primary difference between in vitro/in situ versus in vivo, the presence of this layer was the likely reason for this differential effect. In summary, the size of the polyethylene glycol linker improved the absorption in vitro and in situ, but interfered with the absorption in vivo. Even though this strategy of increasing the ligand flexibility with the variable size of the polyethylene glycol failed to increase oral absorption in vivo, this approach is likely to be useful for enhanced cellular uptake following intravenous administration of the nanocarriers.
研究领域:
药剂学
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药物递送系统
·
生物医学工程
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2020
·
IF 4.902
Tan Yang,Jianfang Feng,Qian Zhang,Wei Wu,Hailan Mo,Lanzhen Huang,Wei Zhang
A delivery system based on l-carnitine (LC) conjugated chitosan (CS)-stearic acid polymeric micelles has been developed for improving the oral bioavailability of paclitaxel (PTX) through targeting intestinal organic cation/carnitine transporter 2 (OCTN2). Stearic acid grafted chitosan (CS-SA), as micelle skeleton material, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The PTX-loaded micelles were prepared by solvent evaporation-hydration method, and the ligand LC was conjugated onto the micelle surface by anchoring its derivative stearoyl group to the lipophilic core of micelle. The modified polymeric micelles showed regular spherical shapes with small particle size of 157.1 ± 5.2 nm and high drug loading capacity of 15.96 ± 0.20 wt%, and the micelle stability in water was supported by low critical micelle concentration of 14.31 ± 0.21 μg/ml. The drug-loaded micelles presented a slow and incomplete in vitro release, and the pharmacokinetic studies indicated the micelle carriers increased the relative bioavailability of PTX to 165.8% against the commercial formulation. The enhancement effect on intestinal absorption was also confirmed by the intracellular uptake of Caco-2 cells. The proposed micelle carrier system manifested a prospective tool for oral drug delivery.
研究领域:
药剂学
·
药物递送系统
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2026
·
IF 12.6
Haihan Sun,Jingxin Gou,Xiaoshuang Bi,Jiayin Song,Boyuan Liu,Xiaoyu Jin,Bowen Sui,Xiangqun Jin
Our previous research identified that an oral mPEG- b -PCL polymeric micelle (PM) maintained satisfactory integrity but exhibited limited transcytosis efficiency. To enhance transcytosis and enable ROS-responsive release, we developed a series of hybrid PMs by blending a synthesized L-carnitine-grafted, thioketal-linked LC-PEG 5k -TK-PCL 7k polymer with mPEG 5k -PCL 7k . These hybrid PMs, similar in particle size (120 nm) and drug loading (10%) to the PM composed of pure mPEG 5k -PCL 7k (5-7E), retained good stability in SGF and SIF. However, the hybrid PM with a 40% LC-PEG 5k -TK-PCL 7k proportion showed reduced integrity and penetration in mucus layer. In Caco-2/E12 (7:3) cells, the hybrid PM with a 20% LC-PEG 5k -TK-PCL 7k proportion (20%Hybrid 5-7E) demonstrated superior uptake, low cytotoxicity, and a 3.37-fold higher transcytosis than that of 5-7E. In 4T1 cells, prepared PMs exhibited similar uptake but hybrid PMs showed obvious ROS-responsive dissociation and cytotoxicity. The in vivo integrity and biocompatibility of 20%Hybrid 5-7E were confirmed by plasma concentration and hemolysis test, and the bio-distribution results demonstrated its tumor accumulation. Pharmacokinetics revealed a 10-fold increase in docetaxel (DTX) bioavailability due to the 20%Hybrid 5-7E encapsulation. Consequently, orally administered 20%Hybrid 5-7E (DTX 40 mg/kg) achieved comparable antitumor activity but reduced systemic toxicity relative to intravenously injected DTX solution (10 mg/kg) in 4T1 tumor-bearing BALB/c mice.
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DOI
PubMed
高影响因子
BIOPHARMACEUTICS & DRUG DISPOSITION
·
2017
·Vol. 38
·期 9
·526-534
·
IF 2.091
Liping Li,Yayun Weng,Wei Wang,Mengru Bai,Hongmei Lei,Hui Zhou,Huidi Jiang
Sulpiride, a selective dopamine D2 receptor blocker, is used widely for the treatment of schizophrenia, depression and gastric/duodenal ulcers. Because the great majority of sulpiride is positively charged at physiological pH 7.4, and ~70% of the dose recovered in urine is in the unchanged form after human intravenous administration of sulpiride, it is believed that transporters play an important role in the renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride. The results demonstrated that sulpiride was a substrate of human carnitine/organic cation transporter 1 (hOCTN1) and 2 (hOCTN2), human organic cation transporter 2 (hOCT2), human multidrug and toxin efflux extrusion protein 1 (hMATE1) and 2-K (hMATE2-K). Sulpiride accumulation from the basolateral (BL) to the apical (AP) side in MDCK-hOCT2/pcDNA3.1 cell monolayers was much greater than that in MDCK-hOCT2/hMATE1 cells, and cimetidine dramatically reduced the intracellular accumulation of sulpiride from BL to AP. In addition, the accumulation of sulpiride in mouse primary renal tubular cells ( m PRTCs) was markedly reduced by inhibitors of Oct2 and Octns. The results implied that OCTN1, OCTN2, OCT2, MATE1 and MATE2-K probably contributed to the renal transfer of sulpiride, in which OCT2 mediated the uptake of sulpiride from the bloodstream to the proximal tubular cells, while MATEs contributed to the sulpiride efflux from the proximal tubular cells to the renal lumen, and OCTNs participated in both renal secretion and reabsorption.
研究领域:
药理学
·
肾病学
·
药物代谢
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2024
·
IF 4.8
Mingyang Chen,Yaodong Yi,Binxin Chen,Hengbin Zhang,Minlei Dong,Luexiang Yuan,Hui Zhou,Huidi Jiang,Zhiyuan Ma
Doxorubicin (DOX) is a widely used antitumor agent; however, its clinical application is limited by dose-related organ damage. Because organic cation/carnitine transporters (OCTN1 and OCTN2), which are critical for DOX uptake, are highly expressed in hepatocytes, we aimed to elucidate the role of these transporters in hepatic DOX uptake. The results indicated that inhibitors and RNA interference both significantly reduced DOX accumulation in HepG2 and HepaRG cells, suggesting that OCTN1/2 contribute substantially to DOX uptake by hepatocytes. To determine whether metformin (MET, an inhibitor of OCTN1 and OCTN2) ameliorates DOX-induced hepatotoxicity, we conducted in vitro and in vivo studies. MET (1–100 μM) inhibited DOX (500 nM) accumulation and cytotoxicity in vitro in a concentration-dependent manner. Furthermore, intravenous MET administration at 250 or 500 mg/kg or by gavage at 50, 100, or 200 mg/kg reduced DOX (8 mg/kg) accumulation in a dose-dependent manner in the mouse liver and attenuated the release of alanine aminotransferase, aspartate aminotransferase, and carboxylesterase 1. Additionally, MET reduced the distribution of DOX in the heart, liver, and kidney and enhanced the urinary elimination of DOX; however, it did not increase the nephric toxicity of DOX. In conclusion, our study demonstrated that MET alleviates DOX hepatotoxicity by inhibiting OCTN1- and OCTN2-mediated DOX uptake in vitro (mouse hepatocytes and HepaRG or HepG2 cells) and in mice.
研究领域:
药理学
·
毒理学
·
肿瘤学
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产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2020
·
IF 4.96
Ping Li,Yuqing Wang,Jun Luo,Qingquan Zeng,Miaojuan Wang,Mengru Bai,Hui Zhou,Jinhai Wang,Huidi Jiang
Inflammatory bowel diseases (IBD) are characterized by chronic relapsing disorders of the gastrointestinal tract. OCTN2 (SLC22A5) and its substrate l -carnitine ( l -Car) play crucial roles in maintaining normal intestinal function. An aim of this study was to delineate the expression alteration of OCTN2 in IBD and its underlying mechanism. We also investigated the impact of OCTN2 on IBD progression and the possibility of improving IBD through OCTN2 regulation. Our results showed decreased OCTN2 expression levels and l -Car content in inflamed colon tissues of IBD patients and mice, which negatively correlated with the degree of colonic inflammation in IBD mice. Mixed proinflammatory cytokines TNF-α, IL-1β and IFNγ downregulated the expression of OCTN2 and subsequently reduced the l -Car content through PPARγ/RXRα pathways in FHC cells. OCTN2 silencing reduced the proliferation rate of the colon cells, whereas OCTN2 overexpression increased the proliferation rate. Furthermore, the ability of PPARγ agonist, luteolin , to increase OCTN2 expression resulted in the alleviation of colonic inflammatory responses. In conclusion, OCTN2 was downregulated in IBD by proinflammatory cytokines via the PPARγ/RXRα pathways, which reduced l -Car concentration and subsequently induced IBD deterioration. Upregulation of OCTN2 by the PPARγ agonist alleviated colonic inflammation. Our findings suggest that, OCTN2 may serve as a therapeutic target for IBD therapy.
研究领域:
胃肠病学
·
免疫学
·
药理学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2023
·
IF 5.1
Yaodong Yi,Hengbin Zhang,Mingyang Chen,Binxin Chen,Yingchun Chen,Ping Li,Hui Zhou,Zhiyuan Ma,Huidi Jiang
Doxorubicin (DOX) has been widely used to treat various tumors; however, DOX-induced cardiotoxicity limits its utilization. Since high accumulation of DOX in cardiomyocytes/mitochondria is the key reason, we aimed to clarify the mechanisms of DOX uptake and explore whether selectively inhibiting DOX uptake transporters would attenuate DOX accumulation and cardiotoxicity. Our results demonstrated that OCTN1/OCTN2/PMAT (organic cation/carnitine transporter 1/2 or plasma membrane monoamine transporter), especially OCTN2, played crucial roles in DOX uptake in cardiomyocytes, while OCTN2 and OCTN1 contributed to DOX transmembrane transport in mitochondria. Metformin (1–100 μM) concentration-dependently reduced DOX (5 μM for accumulation, 500 nM for cytotoxicity) concentration and toxicity in cardiomyocytes/mitochondria via inhibition of OCTN1-, OCTN2- and PMAT-mediated DOX uptake but did not affect its efflux. Furthermore, metformin ( iv : 250 and 500 mg/kg or ig : 50, 100 and 200 mg/kg) could dose-dependently reduce DOX (8 mg/kg) accumulation in mouse myocardium and attenuated its cardiotoxicity. In addition, metformin (1–100 μM) did not impair DOX efficacy in breast cancer or leukemia cells. In conclusion, our study clarified the role of multiple transporters, especially OCTN2, in DOX uptake in cardiomyocytes/mitochondria; metformin alleviated DOX-induced cardiotoxicity without compromising its antitumor efficacy by selective inhibition of multiple transporters mediated DOX accumulation in myocardium/mitochondria.
研究领域:
药理学
·
心脏病学
·
肿瘤学
·
细胞生物学
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Hao Zhi,Zhongyan Wang,Xinyue Zhu,Wenhan Wu,Lu Yang,Yidong Dai,Zehua Wang,Ling Jiang,Yongmei Tan,Xiaodong Liu,Li Liu
Liver failure often causes hepatic encephalopathy, partly due to dysregulation in cerebral energy metabolism. Carnitine and acetylcarnitine play essential roles in energy metabolism by transporting fatty acids from the cytosol into mitochondria, whose transport across the blood-brain barrier (BBB) is primarily mediated by organic cation transporters (OCTs) and organic cation/carnitine transporters (OCTNs). This study aimed to investigate whether liver injury alters the expression of OCTs and OCTNs at the BBB, leading to decreased cerebral carnitine and acetylcarnitine levels and impaired energy metabolism using thioacetamide (TAA)-induced chronic liver injury (CLI) rats. The results showed that CLI significantly downregulated the expression of OCT1, OCT2, and OCTN2 at the BBB, decreased cerebral carnitine/acetylcarnitine levels, and increased the ADP/ATP ratio. Elevated plasmic levels of chenodeoxycholic acid (CDCA) and 17β-estradiol (E2) were detected in CLI rats. In hCMEC/D3 cells, E2 downregulated the expression of OCT2 and OCTN2, which was attenuated by the estrogen receptor-α (ER-α) inhibitor and silencing. CDCA downregulated the expression of OCT1 and OCTN2, which was reversed by the farnesoid X receptor (FXR) inhibitor and silencing. These in vitro findings were confirmed in rats treated with CDCA or E2. Additionally, HEK-293-OCT1 and HEK-293-OCT2 cells demonstrated uptake of carnitine and acetylcarnitine, with uptake in HEK-293-OCT2 cells being 6-fold and 14-fold higher, respectively, than in HEK-293-OCT1 cells. In conclusion, TAA-induced CLI downregulated the expression of OCT1, OCT2, and OCTN2 at the BBB via activating both E2/ER-α and CDCA/FXR pathways, leading to decreased cerebral carnitine and acetylcarnitine levels, disrupted energy metabolism, and contributing to hepatic encephalopathy.
研究领域:
医学
·
神经科学
·
药理学
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产品关联
DOI
PubMed
高影响因子
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