Nanomedicine
·
2024
·
IF 4.7
Shuhui Li,Yuansheng Liu,Xiaojun Sui,Yuzhen Zhuo,He Siqi,Zhang Sijia,Zhang Hui,Li Dihua,Zhang Dapeng,Yang Lei
Aim: To evaluate the anti-pancreatic cancer effect of novel Tubeimoside I multifunctional liposomes combined with gemcitabine.Methods: Liposomes were prepared through the thin film hydration method, with evaluations conducted on parameters including encapsulation efficiency (EE%), particle size, polydispersity index (PDI), zeta potential (ZP), storage stability, and release over a 7-day period. The cellular uptake rate, therapeutic efficacy in vitro and in vivo and the role of immune microenvironment modulation were evaluated.Results: The novel Tubeimoside I multifunctional liposomal exhibited good stability, significant anti-cancer activity, and immune microenvironment remodeling effects. Furthermore, it showed a safety profile.Conclusion: This study underscores the potential of Novel Tubeimoside I multifunctional liposomal as a promising treatment option for pancreatic cancer.
研究领域:
药理学
·
肿瘤学
·
药物递送系统
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DOI
PubMed
高影响因子
Applied Materials Today
·
2026
·
IF 7
Pingan Li,Xiaodan Chen,Jingyang Su,Qin Zhang,Lin Lin
A ROS-responsive degradable hydrogel is developed for localized breast cancer therapy. • The hydrogel integrates MnO 2 -mediated chemodynamic therapy with gemcitabine chemotherapy. • Tumor microenvironment-triggered ROS generation accelerates hydrogel degradation and drug release. • The self-amplifying therapeutic cascade enhances antitumour efficacy with favourable biosafety. Breast cancer therapy remains limited by systemic side effects, intratumoral drug accumulation and tumor recurrence, highlighting the need for effective localized treatment strategies. Herein, we develop a reactive oxygen species (ROS)-responsive degradable hydrogel for localized chemodynamic-chemotherapeutic breast cancer therapy. Bovine serum albumin-templated MnO 2 (BM) nanoparticles and gemcitabine (Gem) are incorporated into a thiol-norbornene photocrosslinked polyethylene glycol (PEG) network containing ROS-cleavable thioketal (TK) linkers. Such a hydrogel serves not only as a local drug depot, but also a tumor microenvironment-activated therapeutic system. Within this microenvironment, MnO 2 consumes endogenous glutathione (GSH) and reacts with hydrogen peroxide (H 2 O 2 ) to generate Mn 2+ and hydroxyl radicals (·OH), inducing oxidative damage and perturbing tumour redox homeostasis. The resulting ROS further cleave TK linkers, accelerating hydrogel degradation and Gem release. This self-amplifying feedback couples chemodynamic therapy with chemotherapy, enabling localized, stimuli-responsive drug delivery and enhanced antitumour efficacy. In vitro and in vivo evaluations confirm significant tumor suppression and favourable biosafety. These findings highlight a microenvironment-responsive hydrogel platform for regional combination therapy of breast cancer. Download: Download high-res image (207KB) Download: Download full-size image A ROS-responsive degradable hydrogel is designed for localized chemo-chemodynamic breast cancer therapy. BSA-templated MnO 2 nanoparticles and gemcitabine are encapsulated within a thiol-norbornene photocrosslinked PEG hydrogel containing ROS-cleavable thioketal linkers. After implantation at the tumor site, MnO 2 reacts with tumor-overexpressed glutathione and hydrogen peroxide to generate Mn 2+ and hydroxyl radicals, thereby depleting intracellular antioxidants and enhancing chemodynamic therapy. The elevated ROS simultaneously cleave thioketal linkers, triggering hydrogel degradation and accelerating gemcitabine release. This tumor microenvironment-activated cascade integrates ROS-amplified chemodynamic therapy with localized chemotherapy, achieving potent tumor cell killing and improved therapeutic safety.
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高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Jia Liu,Senlin Li,Hong Zhou,Mengheng Wang,Chengliang Zhang,Cheng Tian,Yue Xu,Mengxuan Wang,Xin Li,Qing Li,Ming Xiang
Gemcitabine is a widely employed first-line chemotherapeutic drug for pancreatic cancer (PCa). However, the rapid emergence of gemcitabine resistance poses a major clinical hurdle. Here, we identified REG3A as a crucial determinant of poor prognosis in PCa. Notably, REG3A was upregulated in tumor tissues from clinical gemcitabine-resistant PCa patients. Through comprehensive in vitro cellular assays and in vivo studies using Reg3g (the murine homolog of REG3A) knockout mice, we demonstrated that REG3A deficiency sensitized PCa to gemcitabine treatment. Mechanistically, RNA sequencing (RNA-Seq) combined with Protein-Protein Interaction (PPI) analysis revealed that REG3A functioned as an exocytosis protein binds to the novel membrane receptor GPR54. The interaction increased membrane localization of GPR54, which subsequently engaged ARRB2 as a scaffolding molecule, leading to activation of the ERK1/2 pathway and suppression of gemcitabine-induced apoptosis. Moreover, the GPR54 agonist KP10 synergistically enhanced gemcitabine resistance in conjunction with REG3A, while interference with GPR54 or its antagonist KP234 attenuated REG3A-induced gemcitabine resistance. Targeting REG3A or pharmacologically inhibiting its downstream signaling molecules may represent a promising strategy to overcome gemcitabine resistance. Overall, REG3A could serve as a potential biomarker for gemcitabine resistance in PCa, offering a new avenue for therapeutic intervention and patient stratification.
研究领域:
肿瘤学
·
分子生物学
·
癌症药理学
·
信号转导
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE
·
2019
·Vol. 44
·期 5
·1952-1962
·
IF 2.928
Chao Yang,Xian Sun,Hengbing Wang,Ting Lu,Keqing Wu,Yusheng Guan,Jing Tang,Jian Liang,Rongli Sun,Zhongying Guo,Sinian Zheng,Xiaoli Wu,Hesong Jiang,Xi Jiang,Bing Zhong,Xiaobing Niu,Suan Sun,Xinru Wang,Minjian Chen,Guangbo Fu
Bladder cancer (BCa) is a common urinary tract malignancy with frequent recurrences after initial resection. Submucosal injection of gemcitabine prior to transurethral resection of bladder tumor (TURBT) may prevent recurrence of urothelial cancer. However, the underlying mechanism remains unknown. In the present study, ultra‑performance liquid chromatography Q‑Exactive mass spectrometry was used to profile tissue metabolites from 12 BCa patients. The 48 samples included pre‑ and post‑gemcitabine treatment BCa tissues, as well as adjacent normal tissues. Principal component analysis (PCA) revealed that the metabolic profiles of pre‑gemcitabine BCa tissues differed significantly from those of pre‑gemcitabine normal tissues. A total of 34 significantly altered metabolites were further analyzed. Pathway analysis using MetaboAnalyst identified three metabolic pathways closely associated with BCa, including glutathione, purine and thiamine metabolism, while glutathione metabolism was also identified by the enrichment analysis using MetaboAnalyst. In search of the possible targets of gemcitabine, metabolite profiles were compared between the pre‑gemcitabine normal and post‑gemcitabine BCa tissues. Among the 34 metabolites associated with BCa, the levels of bilirubin and retinal recovered in BCa tissues treated with gemcitabine. When comparing normal bladder tissues with and without gemcitabine treatment, among the 34 metabolites associated with BCa, it was observed that histamine change may be associated with the prevention of relapse, whereas thiamine change may be involved in possible side effects. Therefore, by employing a hypothesis‑free tissue‑based metabolomics study, the present study investigated the metabolic signatures of BCa and found that bilirubin and retinal may be involved in the mechanism underlying the biomolecular action of submucosal injection of gemcitabine in urothelial BCa.
研究领域:
肿瘤学
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代谢组学
·
泌尿外科
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DOI
PubMed
高影响因子
Biomedical Materials
·
2023
·Vol. 18
·期 3
·035010
·
IF 4
Fu Zhang,Zhuo Yao,Piaopiao Jin,Mengqiu Xu,Qida Hu,Yuxuan Chen,Risheng Que,Tingbo Liang
Gemcitabine (Gem) has been recommended as a first-line clinical chemotherapeutics for pancreatic ductal adenocarcinoma (PDAC) treatment. Gem treatment could generate chemoresistance associated with abnormal expressions of multiple miRNAs. In the PDAC setting, miRNA-21 (miR-21) overexpression is an important contributing factor of inducing Gem chemoresistance. Inhibition of miR-21 can significantly increase Gem chemosensitivity, which requires an efficient delivery platform to conduct combinational Gem and miR-21 siRNA (miR-21i) therapy. Herein, we synthesized a tumor microenvironment (TME) stimuli-responsive poly(beta-amino ester)s (PBAE)-based polymer nano-prodrug (miR-21i@HA-Gem-SS-P12) that could co-deliver miR-21 siRNA and Gem. The disulfide linkages conjugating GEM onto PBAE can be triggered by elevated reduction stimulus in TME to release the cargo Gem. The hyaluronic acid (HA) fabrication further improved the drug accumulation at the tumor site. Benefiting from the multiple functional improvements and synergism between Gem and miR-21i, the miR-21i@HA-Gem-SS-P12 nano-prodrugs displayed superior tumor inhibition in PDAC in vitro and in vivo. This study established an effective stimuli-responsive nano-prodrug strategy for cooperative treatment with small molecule agents and nucleotide modulators in PDAC.
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PubMed
高影响因子
Materials Today Bio
·
2025
·
IF 10.2
Weiting Jiang,Wei Deng,Qi Chen,Huahua Zhang,Min Zhu,Rongze Wang,Yong Wang
Pancreatic cancers are marked by a highly fibrotic extracellular matrix (ECM) that fosters an immunosuppressive tumor microenvironment (TME), severely limiting the effectiveness of traditional therapies. Emerging evidence suggests that ECM modulation represents a promising strategy to enhance treatment outcomes in pancreatic cancer. Herein, we developed a polymeric nanovesicle for the co-encapsulation and delivery of gemcitabine and prolyl isomerase Pin1 inhibitor sulfopin (Gem/Sul-NP). The engineered Gem/Sul-NP features a compact size of approximately 50 nm, facilitating improved accumulation and penetration within pancreatic tumor tissues. Additionally, the Gem/Sul-NP demonstrates pH-responsive characteristics, undergoing structural disintegration at the acidic pH of 6.5 to achieve controlled drug release in the TME, thereby facilitating synergistic antitumor effects. Sulfopin functions to inhibit pancreatic stellate cells (PSCs) activation, reducing ECM component secretion and disrupting stromal barriers. Besides, it upregulates the expression of the gemcitabine transporter equilibrative nucleoside transporter 1 (ENT1) on tumor cell membranes, thereby enhancing the cellular uptake of gemcitabine and its chemotherapeutic impact. Our in vivo studies confirmed that Gem/Sul-NP treatment effectively remodeled the immunosuppressive TME. When combined with anti-PD-1 therapy, this approach significantly increased CD8 + IFNγ + T cell infiltration, indicating its potential to create favorable conditions for synergistic chemoimmunotherapy against pancreatic cancers.
研究领域:
肿瘤学
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纳米技术
·
药剂学
·
免疫学
·
生物化学
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DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Hongrui Fan,Hongyi Chen,Haolin Song,Chufeng Li,Yu Wang,Zhenhao Zhao,Qin Guo,Xuwen Li,Mingxuan Liu,Tao Sun,Chen Jiang
KRAS mutations are find in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making PDAC exhibit intrinsic resistance to chemotherapy and reshape the immunosuppressive tumor microenvironment (TME), disappointing the clinically preferred chemotherapy-immunotherapy combination. Standing on the cross point of therapeutic resistance, the aberrant adenosine metabolism contributes greatly to chemo- and immunotherapy tolerance. KRAS mutation-induced over-expression of key enzyme CD39 is believed to be involved in shaping the immunosuppressive TME, as it catalyzes the hydrolysis of extracellular ATP into immunosuppressive adenosine. Meanwhile, the loss of equilibrative nucleoside transporters (ENTs) leads to the accumulation of adenosine and the intracellular delivery difficulty of gemcitabine, further vanishing patients’ hope of benefiting from either chemotherapy or immunotherapy. The key challenge is to modulate the aberrant metabolism, also enhance gemcitabine intracellular delivery. Therefore, ROS-responsive positively-charged polymer B-PDEA is prepared and assembled into polyplexes for loading CD39-down-regulating small interfering RNA. Gemcitabine-loaded albumin is coupled with the polyplexes through enzyme-cleavable peptide, forming the intact nanoparticles for the co-delivery of the first-line chemotherapeutic drug and CD39-regulating nucleic acid, showing enhanced gemcitabine intracellular delivery and adenosine metabolism regulating capacity. This approach activated antitumor immunity while achieving chemosensitization by changing the metabolic-immune crosstalk of TME, showcasing great potential for PDAC treatment.
研究领域:
纳米医学
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肿瘤学
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药剂学
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分子生物学
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免疫治疗
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药物递送
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生物化学
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DOI
PubMed
高影响因子
Materials
·
2025
·Vol. 18
·期 17
·4165
·
IF 3.2
Heng Zhang,Yiping Yang,Shengchao Yang,Yuchang Qin,Xuan Lv,Lin Cui,Wei Jia,Zhiyong Liu
The impact of encapsulating gemcitabine (GEM) into nanoparticles on its delivery remains underexplored, with the potential benefits of targeted drug delivery and stimuli-responsive release yet to be fully clarified. Herein, we designed a near-infrared (NIR) light-responsive polymeric nanoparticle, ZnPc@P(PEG-CMA-TKGEM), which integrates reactive oxygen species (ROS) generation and cell imaging capabilities. The self-assembled polymeric micelles exhibit a hydrodynamic size of ~134 nm. Under NIR irradiation, the cumulative drug release rate reaches 51% within 48 h, which is three times higher than that of the non-irradiated control group. In cytotoxicity assays, the cell viability of the NIR-irradiated drug-loaded group is approximately 17%, while that of the NIR-irradiated blank group (without drug loading) remains above 80%. These results confirm that the nanocarriers successfully deliver GEM to target cells and achieve controlled drug release via NIR stimulation.
研究领域:
纳米医学
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癌症治疗
·
药物递送系统
·
高分子化学
·
光动力治疗
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DOI
PubMed
高影响因子
LANGMUIR
·
2026
·
IF 4.4
Jiayi Zuo,Shuhui Qu,Haoping Long,Ting Yuan,Jinqiu Liang,Feng Jiang
To overcome multidrug resistance (MDR) in chemotherapy, a redox-responsive self-assembling nanoprodrug was developed for codelivering gemcitabine (Gem) and the P-glycoprotein (P-gp) inhibitor quinine (Qu). Initially, Gem and Qu were conjugated via a disulfide bond to form the Gem-Qu (GQ) prodrug, but its poor self-assembly capability (forming unstable nanoaggregates) limited its further use. To address this problem, GQ was modified using 3,3′-dithiodipropionic acid or adipic acid to improve the aqueous solubility, yielding GQ-S and GQ-C, respectively. It is noteworthy that both GQ-S and GQ-C could self-assemble into spherical nanoparticles (GQ-S NPs and GQ-C NPs) with uniform size and excellent stability. GQ-S NPs exhibited a hydrodynamic diameter of approximately 147.5 nm, while GQ-C NPs were around 180.5 nm, both with low polydispersity indices. Under tumor-mimicking redox conditions (elevated glutathione or H2O2), GQ-S NPs released approximately 30% of Gem and 48% of Qu simultaneously, whereas Gem release from GQ-C NPs remained below 10%, confirming the enhanced dual redox-responsiveness of GQ-S NPs. Cellular uptake in U251 and U87 glioma cells was efficient for both nanoparticles. GQ-S NPs demonstrated greater cytotoxicity, with an IC50 of 1.560 ± 0.123 μM in U251 cells─7-fold and 2.7-fold lower than that of free Gem and GQ-C NPs, respectively. Mechanistic studies revealed that GQ-S NPs induced apoptosis and markedly suppressed P-gp expression, and promoted intracellular Gem accumulation. In summary, GQ-S NPs integrate the advantages of carrier-free design, low toxicity, high stability, and redox-responsive release, offering a promising strategy for targeted combination therapy in drug-resistant glioblastoma.
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PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2022
·
IF 5.062
Mengfei Li,Hongyu Chen,Dingchuan Peng,Xuehan Lu,Jianping Kong,Shujun Luo,Shiqi Li,Chunlu Tan,Ying Wang
A biodegradable drug delivery system with pH-sensitive property holds vast promise for the improvement of gemcitabine (GEM) in pancreatic cancer cells. Here, a cationic pH-sensitive liposome containing GEM with FU coating (pPSL-FU-GEM, DOTAP: CHEMS : Chol: DSPE-mPEG2000) was designed to improve the bioavailability and efficacy of GEM. After entering the acidic environment of cells, pPSL-FU-GEM could release gemcitabine through an endocytic escape mechanism, preventing it from being degraded by enzymes. The negatively charged fucoidan (FU), which was separated and purified by anion exchange column purification, could target to pancreatic cancer cells and shed, resulting in liposomes uptake by cells. Release studies and intracellular trafficking studies showed that pPSL-FU-GEM released more drug than non-pH-sensitive liposomes in vitro . Meanwhile, pPSL-FU-GEM also showed better anti-proliferative activity than free gemcitabine in pancreatic cancer cells. Overall, we demonstrated the potential of FU-coating pH-sensitive liposomes containing gemcitabine and the drug delivery function in pancreatic cancer cells.
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高影响因子
Journal of Materials Chemistry B
·
2019
·Vol. 8
·期 2
·332-342
·
IF 5.047
Huihui Shi,Ming Xu,Jianhua Zhu,Yang Li,Zhiyu He,Yuxia Zhang,Qunwei Xu,Yimin Niu,Yang Liu
Recently, ultra-small platinum nanoparticles (USPtNs) have been found that can kill cancer cells by leaching Pt ions into acidic organelles, such as cell endosomes or lysosomes. Unfortunately, tumor-specific accumulation is difficult to achieve with such platinum nanodrugs of less than 5 nm due to their short half-life in vivo and broad range of toxicity to normal tissues. Programmable multi-drug release for combinational chemotherapy by hierarchical nanostructures provides a promising solution for cancer-targeted therapy. Herein, we demonstrated a pH/redox dual stimuli-responsive clustered nanoparticle as a vehicle for simultaneously delivering USPtNs and gemcitabine (GEM) to treat non-small-cell lung cancer. The clustered nanoparticle (denoted as GP-NA) was composed of disulfide-bond-containing GEM-grafted copolymers (PEG-b-P(LL-g-GEM)), pH-sensitive polypeptides (OAPI), and USPtNs. Such a hybrid nanosystem completes multiple tasks inside cancer cells, which include the generation of cytotoxic Pt ions in response to lysosomal acidic environments and the subsequent release of GEM in cytoplasmic reduction environments. Compared with non-acid-sensitive nanoparticles or free drugs, GP-NA exhibited cumulative and enhanced anti-tumor efficacy in vivo, which may be attributed to the simultaneous inhibition of ribonucleotide reductase and DNA replication in nuclei by the GEM and Pt ions. Together, our work provides a promising strategy in the co-delivery of USPtNs and GEM for precision cancer chemotherapy.
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 20
·12624
·
IF 6.208
Shanming Zhang,Fen Zheng,Kaige Liu,Shengke Liu,Tonghu Xiao,Yabin Zhu,Long Xu
Mitochondrial DNA and nuclear DNA are essential genetic material which play an important role in maintaining normal metabolism, survival, and proliferation of cells. Constructing a mitochondria-targeting stimuli-responsive nano-drug delivery system releasing chemotherapeutic agents in a stepwise response manner and destroying mitochondrial DNA and nuclear DNA simultaneously is an effective way to improve the anti-tumor effect of chemotherapeutic agents. In this study, a new mitochondria-targeting pH/ROS dual-responsive block copolymer TPP-PEG2k-b-(BS-AA)n(P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-b-(BS-AA)n(P2), pH single-responsive copolymer (mPEG2k-b-(AH-AA)n(P3), ROS single-responsive copolymer mPEG2k-b-(SA-TG)n(P4), and non-responsive copolymer mPEG-b-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Anticancer chemotherapeutic agent gemcitabine (GEM) or fluorescent substance Nile Red (NR) were loaded in the polymer micelles. Results of the mitochondrial colocalization experiment indicate that (5-carboxypentyl)(triphenyl)phosphonium bromide (TPP)-functionalized P1 micelles could be efficiently targeted and located in mitochondria. Results of the cellular uptake experiment showed that pH/ROS dual-responsive GEM-loaded P1 and P2 micelles have faster internalized and entry nucleus rates than single-responsive or non-responsive GEM-loaded micelles. The in vitro release experiment suggests pH/ROS dual-responsive GEM/P1 and GEM/P2 micelles have higher cumulative release than single-responsive GEM/P3 and GEM/P4 micelles. The in vitro cytotoxic experiment shows that the mitochondria-targeted dual-responsive GEM/P1 micelles had the lowest IC50 values, and the cytotoxic effect of dual-responsive GEM/P2 micelles was superior to the single-responsive and non-responsive drug-loaded micelles.Keywords:mitochondria-targeted;pH/ROS dual-responsive;acetal;thioether;TPP
研究领域:
药学
·
纳米技术
·
癌症研究
·
药物递送系统
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）