International Journal of Biological Sciences
·
2024
·
IF 8.2
Peisen Zheng,Yiqun Xia,Xin Shen,Hui Lu,Yinghua Chen,Chenxin Xu,Chenyu Qiu,Yafei Zhang,Peng Zou,Ri Cui,Xiaoying Huang
Lung cancer is one of the most lethal diseases in the world. Although there has been significant progress in the treatment of lung cancer, there is still a lack of effective strategies for advanced cases. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, has achieved much attention due to its antitumor properties. Nevertheless, the use of lenvatinib is restricted by the characteristics of poor efficacy and drug resistance. In this study, we assessed the effectiveness of lenvatinib combined with thioredoxin reductase 1 (TrxR1) inhibitors in human lung cancer cells. Our results indicate that the combination therapy involving TrxR1 inhibitors and lenvatinib exhibited significant synergistic antitumor effects in human lung cancer cells. Moreover, siTrxR1 also showed significant synergy with lenvatinib in lung cancer cells. Mechanically, we demonstrated that ROS accumulation significantly contributes to the synergism between lenvatinib and TrxR1 inhibitor auranofin. Furthermore, the combination of lenvatinib and auranofin can activate endoplasmic reticulum stress and JNK signaling pathways to achieve the goal of killing lung cancer cells. Importantly, combination therapy with lenvatinib and auranofin exerted a synergistic antitumor effect in vivo . To sum up, the combination therapy involving lenvatinib and auranofin may be a potential strategy for treating lung cancer.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2026
·
IF 5.9
Lujian Zhu,Hui Chen,Qiusheng Guo,Chao Ren,Peifei Shi,Qin Wang,Yifei Hu,Zhiyi Fan,Yejin Xu,Dongdong Lin,Haijun Chen
Constructed a dual-functional nano-delivery platform Gel@LTNPS. • LTNPS exhibited excellent physicochemical properties. • The Gel@LTNPS hydrogel showed optimal performance. • In vitro and in vivo studies confirmed that Gel@LTNPS significantly inhibited H22 HCC cell viability and tumor proliferation , with no obvious systemic toxicity. Hepatocellular carcinoma (HCC) remains a leading cause of malignancy-related mortality worldwide, primarily due to the high incidence of postoperative recurrence and the absence of standardized adjuvant therapeutic protocols. While lenvatinib (LT) is established as a first-line targeted therapy for advanced HCC, its clinical efficacy is frequently compromised by poor aqueous solubility and significant systemic adverse effects. To bridge this therapeutic gap, we developed a dual-functional nano-delivery platform, designated as Gel@LTNPS, which integrates rapid localized hemostasis with sustained, targeted antitumor activity for postoperative wound management. In this study, pH-sensitive nanoparticles (LTNPS) were successfully fabricated using the amphiphilic copolymer PAE-PEG-NH 2 via ultrasonic emulsification, achieving a high drug loading (DL) rate of 38.9% and an encapsulation efficiency (EE) of 73.9%. These nanoparticles were subsequently incorporated into a gelatin/hyaluronic acid (Gel-HA) hydrogel scaffold through covalent cross-linking. Physicochemical analysis demonstrated that LTNPS exhibit highly sensitive pH-dependent release kinetics, with 67.3% of LT released at a pH of 5.5 (simulating the acidic tumor microenvironment) compared to only 18.3% at physiological pH 7.4 within 96 h. The optimized Gel@LTNPS formulation (containing 15% gelatin) exhibited superior swelling properties, a controlled biodegradation profile of 21 days, and a robust compressive strength of 0.13 MPa, satisfying the mechanical prerequisites for surgical applications. Functional evaluations in mouse tail-bleeding models confirmed that Gel@LTNPS significantly expedited the coagulation process and minimized blood loss, demonstrating hemostatic performance equivalent to clinical-grade gelatin. Furthermore, in vitro and in vivo assays against H22 HCC models revealed that the platform effectively suppressed tumor cell viability and inhibited proliferation, as evidenced by a marked reduction in proliferating cell nuclear antigen (PCNA) expression. Crucially, the platform exhibited an excellent biosafety profile, with no observable systemic toxicity or histopathological damage to major organs. Collectively, this study offers a sophisticated strategy for the postoperative management of HCC by combining localized wound care with microenvironment-responsive chemotherapy, presenting significant potential for clinical translation.
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Mengmeng Dong,Yumeng Liu,Yuting Xiao,Qingqing Wu,Mingjing Guan,Zunqiang Xiao,Junwei Liu,Lidong Cao,Yi Lu
Hepatocellular carcinoma (HCC) is one of the most prevalent and aggressive forms of liver cancer, with limited therapeutic options and a high recurrence rate. Traditional treatments include surgery and systemic therapy, but systemic therapy has side effects, such as poor specificity, systemic toxicity, and drug resistance. Herein, we designed a multimodal diagnostic and therapeutic-integrated nanosphere for packaging and delivering lenvatinib (LVN). The system was constructed using a PLGA-PEG polymer and modified by cyclic peptide cRGD with high selectivity and affinity for cancer cell integrins. Next, the system was loaded with lenvatinib (LVN) and IR780 photosensitizer, providing a satisfactory basis for photodynamic therapy/photothermal therapy (PDT/PTT) treatment. The nanoparticles could actively and passively target HCC cells and hydrolyze them in an acidic environment to release photosensitizers and LVN, which played significant roles in diminishing tumor cells. After 808 nm laser irradiation, the PDT and PTT effects induced by IR780 synergistically increased the function of LVN by inducing ferroptosis and apoptosis. In addition, in vivo and in vitro experiments showed that PPR@LVN/IR780 nanoparticles could inhibit the growth of tumors under 808 nm laser irradiation without obvious damage to other organs. At the same time, we also used high-throughput sequencing technology to further explore the underlying mechanisms of the nanoparticles. This work not only provided a liver-targeted drug delivery strategy based on first-line systemic therapy drugs but also provided an efficient and synergistic visualization imaging method for fluorescence imaging (FLI), photoacoustic imaging (PAI), and photothermal imaging (PTI) to realize integrated multimodal diagnosis and treatment.
研究领域:
纳米医学
·
肿瘤学
·
药物递送系统
·
光动力疗法
·
光热疗法
·
分子成像
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 7
·1-18
·
IF 8.1
Wang Sikai,Cheng Hongxia,Li Miaomiao,Gao Dongmei,Wu Haoran,Zhang Shanshan,Huang Yilan,Guo Kun
An increasing evidence supports that cell competition, a vital selection and quality control mechanism in multicellular organisms, is involved in tumorigenesis and development; however, the mechanistic contributions to the association between cell competition and tumor drug resistance remain ill-defined. In our study, based on a contructed lenvitinib-resistant hepatocellular carcinoma (HCC) cells display obvious competitive growth dominance over sensitive cells through reprogramming energy metabolism. Mechanistically, the hyperactivation of BCL2 interacting protein3 (BNIP3) -mediated mitophagy in lenvatinib-resistant HCC cells promotes glycolytic flux via shifting energy production from mitochondrial oxidative phosphorylation to glycolysis, by regulating AMP-activated protein kinase (AMPK) -enolase 2 (ENO2) signaling, which perpetually maintaining lenvatinib-resistant HCC cells’ competitive advantage over sensitive HCC cells. Of note, BNIP3 inhibition significantly sensitized the anti-tumor efficacy of lenvatinib in HCC. Our findings emphasize a vital role for BNIP3-AMPK-ENO2 signaling in maintaining the competitive outcome of lenvitinib-resistant HCC cells via regulating energy metabolism reprogramming; meanwhile, this work recognizes BNIP3 as a promising target to overcome HCC drug resistance.
研究领域:
癌症生物学
·
分子生物学
·
细胞生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2023
·
IF 9.9
Qi Xu,Han Hu,Zhimin Mo,Tianyou Chen,Qianyuan He,Zushun Xu
Lenvatinib (LT), a first-line molecular targeted therapeutic drug for hepatocellular carcinoma (HCC), has been replacing the status of Sorafenib (SF) as the clinically preferred and irreplaceable treatment for a decade. To overcome the low drug utilization and limited single efficacy of LT, ultrasmall copper sulfide nanocrystals (Cu 2-x S NCs), and ultrasmall gold nanoparticle (AuNPs) were evenly wrapped into galactosamine conjugated poly(lactide- co -glycolide) (PLGA) as the drug delivery nanoparticles (CAL@PG) by nanoprecipitation. The CAL@PG NPs exhibited excellent stability under physiological conditions, whereas they released LT rapidly in the unique tumor microenvironment (TME) and high temperature, which could be provided by the near-infrared-II (NIR-II) photothermal effect of Cu 2-x S NCs. Moreover, the temperature elevation, regenerated hydrogen peroxide (H 2 O 2 ), and lower pH of TME could substantially boost the reaction potency of copper Fenton-like chemistry. More importantly, this combined therapy significantly improved the efficacy of LT, provided a multifunctional LT delivery system, and enriched the nanoparticle-augmented multimodal synergistic HCC therapy modality.
研究领域:
药学
·
纳米医学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF BIOMATERIALS APPLICATIONS
·
2025
·
IF 2.5
Yong Jiang,Le Fan,Yunxia Chai,Feng Xiao,Nan Zhu,Bin Yi
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Lenvatinib (LEN) is a potentially effective HCC-targeted drug, but poor water solubility, rapid metabolism, drug resistance, and clinical side effects hinder its satisfactory efficacy. In this study, we proposed to prepare a novel epithelial cell adhesion molecule (EpCAM)/Vimentin dual-targeting modified polyester albumin nanocarriers to load LEN (EpCAM/Vimentin-LEN-ANs) to improve the therapeutic efficacy of the drug for HCC. The results showed that the EpCAM/Vimentin-LEN-ANs had a particle size of (236.08 ± 6.39) nm, a potential of (38.93 ± 7.15) mv, and were characterized by nanovesicles, with an encapsulation rate of (97.57 ± 2.43) % and a drug loading capacity of (11.16 ± 1.75) %. EpCAM/Vimentin-LEN-ANs can specifically target HCC cells and slowly release LEN drugs, thus effectively inhibiting the growth of HCC cells; in addition, they have good anti-tumor effects and biosafety in vivo. In this study, EpCAM/Vimentin-LEN-ANs were successfully prepared, which can carry LEN and then target into HCC cells to achieve precise delivery and release of drugs, improve anti-tumor efficacy and alleviate the toxic side effects of anti-tumor drugs on the organism, which has a better potential for application and clinical translation in the treatment of HCC.
研究领域:
纳米医学
·
肿瘤学
·
药剂学
·
生物工程
·
分子靶向治疗
✓ 已验证
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Wen Luo,Yana Ma,Weijia Zhu,Ruican Nie,Yue Wu,Dongqiu Shan,Shijun Xu,Ho-Young Song,Hongtao Hu
Liver cancer remains a major global public health threat, with high mortality. Lenvatinib is a tyrosine kinase inhibitor that has been used for the treatment of advanced liver cancer. However, its therapeutic efficacy is often limited by severe adverse effects and drug resistance. To overcome these challenge, we developed a biomimetic versatile nanoplatform based on Mn-doped polydopamine (PML@CM). Owing to their homologous tumor-targeting ability and pH-responsive drug release properties, PML@CM nanoparticles effectively improved the biocompatibility of lenvatinib and enhanced its tumor accumulation. Upon exposure to the tumor microenvironment, the released Mn2+ not only triggered chemodynamic therapy through Fenton-like reactions but also enabled magnetic resonance imaging (MRI). In addition, PML@CM nanoparticles exhibited an efficient photothermal conversion performance for tumor photothermal therapy. In conclusion, this nanoplatform provides a promising therapeutic strategy for MRI-enabled synergistic therapy against liver cancer.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CURRENT MOLECULAR MEDICINE
·
2025
·Vol. 25
·期 3
·343-352
·
IF 2.5
Weiqing Feng,Haixiong Zhang,Qing Yu,Hao Yin,Xiaowei Ou,Jie Yuan,Liang Peng
Background The emergence of treatment resistance has hindered the efficacy of targeted therapies used to treat patients with hepatocellular carcinoma (HCC). Objective This study aimed to explore the mechanism of organoids constructed from lenvatinib-resistant HCC cells. Methods Hep3B cell and human HCC organoids were cultured and identified using hematoxylin and eosin staining and Immunohistochemistry. Lenvatinib-sensitive/ resistant Hep3B cells were constructed using lenvatinib (0, 0.1, 1, and 10 μM) and lenvatinib (0, 1, 10, and 100 μM). qRT-PCR and flow cytometry were utilized to deter-mine HCC stem cell markers CD44, CD90, and CD133 expressions. Transcriptome sequencing was performed on organoids. Western blot evaluated Notch pathway-related proteins (NOTCH1 and Jagged) expressions. Furthermore, DAPT, an inhibitor of the Notch pathway, was used to investigate the effects of lenvatinib on resistance or stemness in organoids and human HCC tissues. Results The organoids were successfully cultivated. With the increase of lenvatinib concentration, sensitive cell organoids were markedly degraded and ATP activity was gradually decreased, while there was no significant change in ATP activity of resistant cell organoids. CD44 expressions were elevated after lenvatinib treatment compared with the control group. KEGG showed that lenvatinib treatment of organoids constructed from Hep3B cells mainly activated the Notch pathway. Compared with the control group, NOTCH1 and Jagged expressions elevated, and ATP activity decreased after lenvatinib treatment. However, ATP activity was notably decreased after DAPT treatment. Moreover, DAPT inhibited lenvatinib resistance and the increase in the expressions of CD44 caused by lenvatinib. Besides, 100 μM lenvatinib significantly inhibited the growth and ATP activity of human HCC organoids, and DAPT increased the inhibitory effect of lenvatinib. Conclusion Lenvatinib regulated resistance and stemness in organoids via the Notch pathway.
研究领域:
肿瘤学
·
分子生物学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cancer Cell International
·
2025
·Vol. 25
·期 1
·1-18
·
IF 6
Li Duo,Zhong Qi,Xiao Di,Wang Weifan,Xie Lejing,Peng Mei,Xu Cangcang,Wu Huaying,Li Zhuan,Yang Xiaoping
Background Hepatocellular carcinoma (HCC) is an invasive malignant tumour for which few effective treatment options are currently available. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases used for the treatment of patients with advanced HCC. Although lenvatinib has been proven effective in treating HCC patients, clinical data show that the response rate to lenvatinib is very low and that 76% of HCC patients are insensitive to lenvatinib. Phenformin is a well-known activator of adenosine monophosphate-activated protein kinase (AMPK), which has recently attracted widespread attention because of its anticancer effects. We investigated whether phenformin could enhance the efficacy of lenvatinib in treating HCC and, if so, the underlying mechanisms involved in this process. Methods The anticancer effects of the combination of phenformin and lenvatinib in HCC cells were assessed in vitro and in vivo. First, colony formation, EdU and MTT assays were conducted to measure the viability of the HCC cells. Flow cytometry was used to assess the cell cycle distribution of HCC cells. Then, western blotting (WB) was performed to detect protein expression in HCC cells after various treatments. Immunoprecipitation-mass spectrometry (IP-MS) and co-immunoprecipitation (Co-IP) assays were used to determine the interaction relationships of proteins. In addition, a xenograft model was used to analyze the effects of the different treatments on the proliferation of HCC cells. Immunohistochemistry and western blot assays were conducted to investigate the expression of related proteins in the tissues of the xenograft model. Haematoxylin and eosin (H&E) staining was used to analyze the toxicity to the livers and kidneys of mice. Western blot assays were used to detect protein expression in human HCC samples. Results High expression of platelet-derived growth factor receptor β (PDGFRβ) resulted in the insensitivity of HCC cells to lenvatinib, and PDGFRβ knockdown increased the sensitivity of HCC cells to lenvatinib. Phenformin inhibited the proliferation of HCC cells via AMPK-mediated PDGFRβ degradation. Compared with lenvatinib monotherapy, combined treatment with phenformin and lenvatinib considerably enhanced the anticancer effects both in vivo and in vitro. Mechanistic studies showed that AMPK binds PDGFRβ and promotes its degradation via the c-Cbl-mediated lysosomal pathway. Conclusions Our study reports a novel combined therapy using phenformin and lenvatinib, which can increase the sensitivity of HCC cells to lenvatinib via AMPK-mediated PDGFRβ degradation. Hence, this treatment strategy may provide a personalized approach for treating HCC patients with high PDGFRβ expression and facilitate the development of basic and clinical research on the use of lenvatinib for the treatment of HCC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2019
·
IF 4.833
Gaofei Wei,Liangfeng Huang,Yali Jiang,Yifeng Shen,Zeqian Huang,Yanjuan Huang,Xiaoqi Sun,Chunshun Zhao
The therapeutic efficacy of targeted therapy is dramatically hindered by multidrug resistance (MDR) because of elevated GSH levels. Thus, depletion of intracellular GSH level is highly desirable for targeted-therapeutic agents to reverse tumor drug resistance. In this study, a photosensitive multifunctional conjugate ZnPc-C 8 -Len, in which lenvatinib (a VEGFR inhibitor) is linked to a photosensitizer ZnPc through an alkyl chains, was synthesized to realize photodynamic therapy to reverse multidrug resistance and enhanced antitumor therapy. Upon the irradiation, ZnPc-C 8 -Len could generate ROS to deplete intracellular GSH. The decreased GSH would enhance apoptotic cell death by Bcl-2/caspase 3 pathway and reduce expression of P-gp to reverse lenvatinib resistance. Moreover, through PEG 2000 -PLA 2000 encapsulation, ZnPc-C 8 -Len NPs displayed significantly enhanced tumor accumulation and excellent in vivo antitumor activity. And the fluorescence characteristics of ZnPc-C 8 -Len could monitor the changes of nanoparticles in vivo in real time to guide when and where to conduct the subsequent therapy. As a result, conjugate ZnPc-C 8 -Len had an outstanding capability to enhance synergistic therapy of multidrug-resistant cancer by glutathione depletion. And the approach reported here provide a promising strategy in development of conjugate integrated targeted therapy with photodynamic therapy to reverse targeted drug multidrug resistance and enhance synergistic therapy.
研究领域:
肿瘤学
·
药理学
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2026
·
IF 3.4
Jing Yang,Jiaxin Geng,Yue Yin,Kangle Wang,Leyao Tian,Jingyi Wang,Huijie Jia,Lei Wang,Yongxi Zhang,Tiesuo Zhao
BackgroundLenvatinib is a first-line multi-target tyrosine kinase inhibitor for hepatocellular carcinoma (HCC) that exerts anti-angiogenic effects by blocking VEGF signaling. However, its clinical efficacy is often compromised by adaptive resistance. Nifuroxazide, an anti-diarrheal agent, has been identified by our group as a potent inhibitor of PD-L1 expression in HCC.ObjectiveThis study aimed to evaluate the therapeutic potential and underlying molecular mechanisms of nifuroxazide combined with lenvatinib against HCC.MethodsIn vitro, HCC cell proliferation, colony formation, and migration were assessed, and Western blot was used to detect p-STAT3, STAT3, PD-L1, and VEGF levels. In vivo, antitumor efficacy was evaluated in mouse xenograft models. Tumor tissues were analyzed by immunohistochemistry, TUNEL, and H&E staining, while flow cytometry was used to measure CD4+ and CD8+ T-cell proportions in the tumor microenvironment, peripheral blood, and spleen.ResultsThe combination synergistically inhibited HCC cell proliferation and migration, and downregulated PD-L1, p-STAT3, and VEGF expression. It also markedly suppressed tumor growth, induced apoptosis, and enhanced CD4+ and CD8+ T-cell infiltration and distribution.ConclusionsNifuroxazide potentiates lenvatinib-induced antitumor activity by regulating the STAT3/PD-L1 axis and enhancing antitumor immune responses. This combination provides a promising therapeutic strategy for HCC.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Omega
·
2021
·
IF 3.512
Jingjing Zong,Hao Peng,Xin Qing,Zhe Fan,Wenjing Xu,Xuanlong Du,Ruihua Shi,Yewei Zhang
Combination therapy such as photodynamic therapy (PDT)-enhanced chemotherapy is regarded as a promising strategy for cancer treatment. Boron-dipyrromethene (BODIPY), as close relatives of porphyrins, was widely used in PDT. However, poor water solubility, rapid metabolism by the body and lack of targeting limits its clinical application. Lenvatinib, as the first-line drug for molecular-targeted therapy of liver cancer, restricted its clinical application for its side effects. Herein, to achieve the synergy between PDT and chemotherapy, we synthesized two halogenated BODIPY, BDPBr2 and BDPCl2, which were prepared into self-assembly nanoparticles with lenvatinib, and were encapsulated with Pluronic F127 through the nanoprecipitation method, namely, LBPNPs (LBBr2 NPs and LBCl2 NPs). The fluorescence quantum yields of LBPNPs were 0.73 and 0.71, respectively. The calculated loading rates of lenvatinib for LBBr2 NPs and LBCl2 NPs were 11.8 and 10.2%, respectively. LBPNPs can be hydrolyzed under weakly acidic conditions (pH 5.0) to generate reactive oxygen species (ROS), and the release rate of lenvatinib reached 88.5 and 82.4%. Additionally, LBPNPs can be effectively taken up by Hep3B and Huh7 liver cancer cells, releasing halogenated BODIPY and lenvatinib in the acidic environment of tumor cells to enhance the targeting performance of chemotherapeutics. Compared with free lenvatinib and separate halogenated BODIPY, LBPNPs can inhibit tumor growth more effectively through pH-responsive chemo/photodynamic synergistic therapy and significantly promote the cascade of caspase apoptotic protease. This study shows that LBPNPs can be a promising nanotheranostic agent for synergetic chemo/photodynamic liver cancer therapy.
研究领域:
药学
·
纳米技术
·
癌症研究
·
生物医学工程
✓ 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）