查找使用阿拉丁产品的科研文献

Gambogic acid suppresses pancreatic fibrosis via inhibiting YAP1-mediated activation of pancreatic stellate cells

Wei Li,Guangming Li,Yi Wang,Yuxin Zhou

The activation of pancreatic stellate cells (PSCs) and the secretion of inflammatory factors play critical roles in the development of pancreatic fibrosis. While gambogic acid (GA), a flavonoid with anti-tumor properties, has been studied, its role in this process remains unclear. This study demonstrated that GA promoted YAP1 degradation and reduced its nuclear localization, thereby inhibiting PSC activation and the progression of pancreatic fibrosis. GA inhibited PSC proliferation, decreased α -smooth muscle actin ( α -SMA) expression, and reduced lipid droplets in LTC14 and primary mouse PSCs (mPSCs). Additionally, GA suppressed the expression of inflammatory factors [nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3), nuclear factor erythroid 2-related factor 2 (NRF2), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and nuclear factor κ B (NF- κ B)] in PSCs and counteracted the transforming growth factor (TGF)-β-induced increase in these proteins. GA also reduced collagen Ι and tissue inhibitor of metalloproteinase-1 (TΙMP1) expression, thereby attenuating fibrosis. Mechanistically, GA decreased YAP1 expression and nuclear translocation and reversed TGF-β-induced YAP1 upregulation. YAP1 overexpression abrogated GA’s inhibitory effects on PSC activation and inflammation. Furthermore, GA activated the Hippo pathway, increased phosphorylated (p)-LATS1 and p-YAP levels, and promoted ubiquitin-mediated YAP1 degradation. In vivo studies confirmed that GA inhibited dibutyltin dichloride (DBTC)-induced pancreatic fibrosis via suppressing YAP1 and NF- κ B in BALB/c mice. In conclusion, GA activates the Hippo pathway and promotes YAP1 translocation to the cytoplasm, leading to its degradation and subsequent inhibition of PSC activation and fibrosis. These findings highlight the critical role of ubiquitin-mediated YAP1 degradation in regulating PSC activity and offer novel insights into the therapeutic potential of GA for treating pancreatic fibrosis.

A novel dual sensitive polymer-gambogic acid conjugate: synthesis, characterization, and in vitro evaluation

Ke Song,Zhaobo Wang,Xue Liu,Guolin Zhang,Xin Wang,DeFang Ouyang,Mingrui Guo,Lijiang Chen

Currently, bio-simulate drug delivery systems are highly considered for efficient targeting of tumors. Nevertheless, there are some potential problems such as intelligent release efficiency, subsequently, influence cell toxicity and blood circulation stability. A novel type of stimuli-responsive nanoparticle was developed in accordance with the specific tumor microenvironment to deliver gambogic acid (GA). Herein, we successfully connected GA with mPEG via two different sensitive linkages, valine-citrulline (VC) and cystamine. The structure was characterized by ESI-MS, 1H NMR, FT-IR or MALDI-TOF-MS. The mPEG-VC-SS-GA-NPs (PVSG-NPs) were rapidly prepared. The properties of nanoparticles, including solubility, particle size, morphology, and sensitive drug release performance, were investigated. Compared to single sensitive conjugate (mPEG-SS-GA-NPs, PSG-NPs), PVSG-NPs demonstrated greater solubility and higher sensitive release profile. Cytotoxicity test indicated that PVSG-NPs had apparent cytotoxicity on HepG2 cells and reduced cytotoxicity on normal cells. Additionally, PVSG-NPs mainly kill HepG2 cells by inducing early and late apoptosis and restraining the G0/G1 phase proliferation. Albumin adsorption test revealed that the PVSG-NPs had little albumin combination, consequently, enhancing their circulation constancy. In summary, our findings suggested the novel PVSG-NPs capable of being used for tumor targeting and further practical applications.

Ultrasound-triggered drug delivery for glioma therapy through gambogic acid-loaded nanobubble-microbubble complexes

Feng Wang,Lei Dong,Simin Liang,Xixi Wei,Yongling Wang,Liansheng Chang,Kang Guo,Hongwei Wu,Yuqiao Chang,Yaling Yin,Lu Wang,Yu Shi,Fei Yan,Nana Li

Glioma is one of the most common primary brain tumors. Gambogic acid (GA) is widely used in tumor chemotherapy. However, GA has poor water solubility, low bioavailability, and difficult permeability across the blood–brain barrier (BBB), leading to poor efficacy against brain tumors. In our study, we developed negatively charged GA-loaded PLGA nanobubbles [GA/poly(lactic- co -glycolic acid) (PLGA)] and conjugated them onto the surface of cationic lipid microbubbles (CMBs) through electrostatic interactions. The resulting GA/PLGA–CMB complex was characterized for its particle size, distribution, drug encapsulation efficiency, and ultrasound imaging property, revealing a high drug encapsulation efficiency and excellent contrast imaging capability. Importantly, significantly enhanced GA delivery into the brain could be observed after the intravenous administration of GA/PLGA–CMBs combined with low-intensity focused ultrasound (FUS) due to the cavitation from CMBs, which mediated blood–brain barrier (BBB) opening. Taking advantage of the opened BBB, GA/PLGA nanobubbles could be delivered into the tumor. Then, the second FUS irradiation at higher energy was used to induce the cavitation of GA/PLGA nanobubbles, producing the second cavitation on tumor cells, significantly enhancing the ability of GA to enter tumor cells and inhibit tumor growth inhibition efficacy.

Novel Long-Circulating Liposomes Consisting of PEG Modified β-Sitosterol for Gambogic Acid Delivery

Yu Fan,Tang Xinhui

Long-circulating liposome is an effective formulation in field of cancer treatment. However, high expenditure of formulation and high dose of cholesterol severely restrict its application. In this paper, we developed a method by grafting polyethylene glycol 2000 on β-sitosterol succinic anhydride ester to obtain relatively cheap polyethylene glycol-β-sitosterol conjugates, which were used to prepare long-circulating liposome without cholesterol. Gambogic acid which is an effective antitumor ingredient with very short half-life, was used as a model drug to prepare long-circulating liposome in this research. Meanwhile, the characteristics, pharmacokinetics and distribution of this novel long-circulating liposome were also investigated in comparison with other gambogic acid formulations. Polyethylene glycol-β-sitosterol conjugates were synthesized, different liposomal formulations were also prepared by ethanol injection method, and the obtained nanoparticles were characterized by dynamic light scattering and transmission electron microscope. The long-circulating effect, pharmacokinetics and distribution of gambogic acid in rats were also explored. 1HNMR confirmed that polyethylene glycol-β-sitosterol conjugates were synthesized successfully. Novel long-circulating liposome was successfully prepared by ethanol injection method attaining a entrapment efficiency of 89.4%, exhibiting a homogeneous particle size of 245.2 nm and −24.3 mV zeta potential with smooth continuous surface. This novel long-circulating liposome demonstrated better long-circulating effect than ordinary long-circulating liposome. The novel long-circulating liposome as-prepared not only could reduce cost of grafting polyethylene glycol on macromolecular phospholipid, but also no cholestrol in preparation was applied, expanding the application of liposome as a formulation in the field of lowering blood lipid. Therefore, polyethylene glycol-β-sitosterol conjugates are recommended substitute for polyethylene glycol modified phospholipid to prepare long-circulating liposomes.

Pluronic F68-Linoleic Acid Nano-spheres Mediated Delivery of Gambogic Acid for Cancer Therapy

Fang Xiaobin,Xu Yingqi,Wang Shengpeng,Wan Jianbo,He Chengwei,Chen Meiwan

Gambogic acid (GA), a natural compound from gamboge resin, has been introduced as a promising antitumor drug contributing to its broad spectrum of antitumor activity. However, the poor aqueous solubility and short half-life hinder its clinical application. Pluronic F68 (F68) is a well-known amphiphilic block copolymer consisting of hydrophobic propylene oxide units and hydrophilic ethylene oxide. Although F68 has an amphiphilic structure, its short propylene oxide segment limits its dilution stability and drug-loading capacity. To overcome this limitation, we modified F68 by conjugating linoleic acid, a hydrophobic fatty acid, to increase the hydrophilic-hydrophobic interaction and thus improve the stability of F68 nano-spheres. This F68-linoleic acid (F68-LA) conjugate was synthesized and was used to load GA to improve its anticancer effects. GA-loaded F68-LA nano-spheres were stable for 6 days, with a mean diameter of 159.3 nm and zeta potential of −23.2 mV. The entrapment efficiency of GA in F68-LA nano-spheres was as high as 92.0%. Furthermore, F68-LA/GA nano-spheres exhibited an enhanced cytotoxic activity and proapoptotic effect against human ovarian cancer A2780 cells, compared with free GA. Our results showed that the F68-LA/GA nano-spheres might be a promising cancer-targeted drug delivery system in ovarian cancer therapy.

A tumor-targeting gambogic acid-loaded nanovaccine reprograms the tumor microenvironment for enhanced cancer immunotherapy

Ning Wang,Xingzhi Han,Xueying Bai,Zixin Liang,Xinyi Xu,Liuqi Sang,Li Li,Jing Hu,Qun Zhang,Xiaoping Qian

Nanovaccines for co-delivering antigens and adjuvants have demonstrated certain efficacy in cancer immunotherapy. However, these vaccines are challenged by poor biocompatibility, insufficient targeting ability, and attenuated performance in the immunosuppressive tumor microenvironment (TME). In this study, we successfully constructed a cancer cell membrane (CCM)-coated nanovaccine loaded with an active component from traditional Chinese medicine, gambogic acid (GA), using a magnesium/aluminum layered double hydroxide (LDH) as the functional carrier (CCM-LDH@GA). CCM serves as a source of tumor-associated antigens, endowing the nanovaccine with homologous targeting ability and a prolonged circulation time, while the LDH carrier enables efficient loading of GA and facilitates pH-responsive release in the acidic TME, thereby enhancing the therapeutic efficacy of GA while effectively addressing its drawbacks, which include poor solubility, low tumor selectivity, and potential toxicity. In vivo studies in a CT26 colorectal cancer mouse model showed that CCM-LDH@GA exhibits efficient tumor targeting and remodels the immunosuppressive TME by promoting dendritic cell maturation, inhibiting macrophage M2 polarization, and activating T cells, thereby inducing a robust antitumor response. In addition, the combination of the nanovaccine with immune checkpoint inhibitors achieves synergistic therapeutic efficacy with a favorable safety profile. In conclusion, this study presents a robust nanovaccine platform capable of eliciting potent antitumor immunity, demonstrating significant potential for clinical translation in cancer immunotherapy.

Chemodynamic therapy-cooperatively enhanced gambogic acid-iron-doxorubicin nanozymes for chemotherapy sensitization in liver cancer

Liu Chang,He Yanlin,Tang Huimin,Chen Jiayan,Li Jiale,Liu Rubing,Liu Xueli,Chen Hongrang,Ren Chunxia

As a common malignant tumor, achieving better treatment outcomes for liver cancer remains our constant pursuit. To enhance tumor cell killing efficiency, this study designed a nanozyme—gambogic acid-iron-doxorubicin (GAFe@Dox)—that simultaneously improved the tumor microenvironment (TME) and sensitized cells to chemotherapy. Its antitumor efficacy was systematically evaluated using 3D hydrogel cell scaffolds model simulating the human TME. First, transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) confirmed the successful synthesis of GAFe@Dox and verified its peroxidase activity. Cellular experiments demonstrated that GAFe@Dox generated substantial reactive oxygen species (ROS) via the Fenton reaction, synergistically killing tumor cells through multiple pathways with other components. Its killing mechanism was preliminarily validated at the cellular level. Transcriptomic analysis revealed GAFe@Dox effectively regulated signaling pathways including p53, MAPK and so on, further substantiating its mechanism of action. Additionally, we successfully constructed and cultured 3D hydrogel cell scaffolds model, simulating the in vivo 3D environment for cell growth and proliferation, achieving preliminary success. Subsequent validation confirmed that GAFe@Dox effectively penetrated and inhibited cell proliferation while inducing tumor cell apoptosis. This study demonstrated GAFe@Dox’s potent cytotoxic effects through synergistic multi-mechanistic tumor cell killing and established a physiologically relevant drug efficacy evaluation model, offering novel insights for nanozymes therapy research in liver cancer.

Hyaluronic acid-decorated redox-sensitive chitosan micelles for tumor-specific intracellular delivery of gambogic acid

Wei Xu,Honglan Wang,Lihui Dong,Pan Zhang,Yan Mu,Xueyan Cui,Jianping Zhou,Meirong Huo,Tingjie Yin

Introduction: Herein, a hyaluronic acid (HA)-coated redox-sensitive chitosan-based nanoparticle, HA(HECS-ss-OA)/GA, was successfully developed for tumor-specific intracellular rapid delivery of gambogic acid (GA).Materials and methods: The redox-sensitive polymer, HECS-ss-OA, was prepared through a well-controlled synthesis procedure with a satisfactory reproducibility and stable resulted surface properties of the assembled cationic micelles. GA was solubilized into the inner core of HECS-ss-OA micelles, while HA was employed to coat outside HECS-ss-OA/GA for CD44-mediated active targeting along with protection from cation-associated in vivo defects. The desirable redox-sensitivity of HA(HECS-ss-OA)/GA was demonstrated by morphology and particle size changes alongside in vitro drug release of nanoparticles in different simulated reducing environments.Results: The results of flow cytometry and confocal microscopy confirmed the HA-receptor mediated cellular uptake and burst drug release in highly reducing cytosol of HA(HECS-ss-OA)/GA. Consequently, HA(HECS-ss-OA)/GA showed the highest apoptosis induction and cytotoxicity over the non-sensitive (HA(HECS-cc-OA)/GA) and HA un-coated (HECS-ss-OA/GA) controls against A549 NSCLC model both in vitro and in vivo. Furthermore, a diminished systemic cytotoxicity was observed in HA(HECS-ss-OA)/GA treated mice compared with those treated by HA un-coated cationic ones and GA solution.

Dually enhanced phototherapy by gambogic acid and hyperthemia-activated chemotherapy for synergistic breast cancer treatment

Yuhan Wang,Chunyan Yue,Mengyao Zhang,Dazhao Li,Tao Xu,Mengying He,Mengyuan Wang,Yanan Zhao,Zihui Ni,Feng Zhi,Yiqiao Hu,Dawei Ding

Combining chemotherapy and phototherapy (including photodynamic therapy and photothermal therapy) via nanoscale drug delivery systems has been widely explored to improve the therapeutic efficacy of cancers. Nevertheless, deficient reactive oxygen species (ROS) level caused by the excessive antioxidants (e.g., glutathione (GSH)) in tumor cells and thermoresistance mediated by heat shock proteins (HSPs) represent two pivotal obstacles for phototherapy. In addition, limited control on drug release via conventional nanocarriers results in unpredictable side effects of chemotherapeutic drugs. To tackle these problems, a novel phase change material (PCM)-based nanoplatform co-delivering paclitaxel (PTX), IR780 and gambogic acid (GA) was developed via a facile method to achieve chemotherapy synergized by dually-enhanced phototherapy of breast cancers. PCM-based nanoparticles (NPs) revealed favorable particle size and greatly improved photostability of IR780. PCM endowed the NPs with hyperthemia-triggered release of PTX for chemotherapy, which was beneficial to dampen the side effects. Upon the cellular uptake, GA-depleted intracellular GSH and blocked the overexpression of HSP90, which in turn simultaneously increased the ROS level and suppressed thermoresistance to enhance the efficacies of PDT and PTT, respectively. Finally, the dually-energized phototherapy and PTT-activated low-dose PTX-based chemotherapy achieved outstanding antitumor performances in vitro and in vivo. Taken together, via the NIR-activatable PCM-based NPs, a strategy of harnessing a single enhancer to boost the efficacies of dual-modal phototherapy and low-dose chemotherapy has been established for improved cancer treatment and reduced side effects.

Cancer Cell Membrane-Coated Gambogic Acid Nanoparticles for Effective Anticancer Vaccination by Activating Dendritic Cells

Fengli Huang,Qun Zhang,Jie Xiao,Xin Zhang,Xingzhi Han,Xiao Shi,Jing Hu,Li Li,Xiaoping Qian

Purpose Recent studies have shown that traditional Chinese medicine (TCM), such as gambogic acid (GA), is involved in the regulation of tumor immune microenvironment and can be combined with other anti-tumor treatment strategies. Here, we used GA as an adjuvant to construct a nano-vaccine to improve the anti-tumor immune response of colorectal cancer (CRC).Materials and Methods We used a previously reported two-step emulsification method to obtain poly (lactic-co-glycolic acid) /GA nanoparticles (PLGA/GA NPs), and then CT26 colon cancer cell membrane (CCM) was used to obtain CCM-PLGA/GA NPs. This novel nano-vaccine, CCM-PLGA/GA NPs, was co-synthesized with GA as an adjuvant and neoantigen provided by CT26 CCM. We further confirmed the stability, tumor targeting, and cytotoxicity of CCM-PLGA/GA NPs. The regulatory effect on the tumor immune microenvironment, the anti-tumor efficacy, and the combined anti-tumor efficacy with anti-PD-1 monoclonal Antibodies (mAbs) of this novel nano-vaccine was also detected in vivo.Results We successfully constructed the CCM-PLGA/GA NPs. In vitro and in vivo tests showed low biological toxicity, as well as the high tumor-targeting ability of the CCM-PLGA/GA NPs. Besides, we revealed a remarkable effect of CCM-PLGA/GA NPs to activate the maturation of dendritic cells (DCs) and the formation of a positive anti-tumor immune microenvironment.Conclusion This novel nano-vaccine constructed with GA as the adjuvant and CCM providing the tumor antigen can not only directly kill tumors by enhancing the ability of GA to target tumors, but also indirectly kill tumors by regulating tumor immune microenvironment, providing a new strategy for immunotherapy of CRC.

Aminated β-cyclodextrin-grafted Fe3O4-loaded gambogic acid magnetic nanoparticles: preparation, characterization, and biological evaluation

Wei Fang,Ya Ji Dai,Ting Wang,Hai Tao Gao,Peng Huang,Juan Yu,He Ping Huang,Dian Lei Wang,Wei Lu Zong

Based on aminated β-cyclodextrin (6-NH2-β-CD)-grafted Fe3O4 and gambogic acid (GA) clathrate complexes, a nanoparticle delivery system was developed with the aim to achieve low irritation, strong targeting, and high bioavailability of a gambogic acid magnetic nanopreparation. 6-NH2-β-CD grafted onto Fe3O4 MNPs was demonstrated by high-resolution transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, zeta potential, and magnetic measurements. The average particle size of the Fe3O4@NH2-β-CD MNPs was 147.4 ± 0.28 nm and the PDI was 0.072 ± 0.013. The encapsulation efficiency, drug loading, zeta potential, and magnetic saturation values of the Fe3O4@NH2-β-CD MNPs were 85.71 ± 3.47%, 4.63 ± 0.04%, −29.3 ± 0.42 mV, and 46.68 emu g−1, respectively. Compared with free GA, the in vitro release profile of GA from Fe3O4@NH2-β-CD MNPs was characterized by two phases: an initial fast release and a delayed-release phase. The Fe3O4@NH2-β-CD MNPs displayed continuously increased cytotoxicity against HL-60 and HepG2 cell lines in 24 h, whereas the carrier Fe3O4@NH2-β-CD MNPs showed almost no cytotoxicity, indicating that the release of GA from the nanoparticles had a sustained profile and Fe3O4@NH2-β-CD MNPs as a tumor tissue-targeted drug delivery system have great potential. Besides, blood vessel irritation tests suggested that the vascular irritation could be reduced by the use of Fe3O4@NH2-β-CD MNPs encapsulation for GA. The t1/2 and the AUC of the Fe3O4@NH2-β-CD@GA MNPs were found to be higher than those for the GA solution by approximately 2.71-fold and 2.42-fold in a pharmacokinetic study, respectively. The better biocompatibility and the combined properties of specific targeting and complexation ability with hydrophobic drugs make the Fe3O4@NH2-β-CD MNPs an exciting prospect for the targeted delivery of GA.

Gambogic acid-loaded PEG–PCL nanoparticles act as an effective antitumor agent against gastric cancer

Dinghu Zhang,Zhengyun Zou,Wei Ren,Hanqing Qian,Qianfeng Cheng,Liulian Ji,Baorui Liu,Qin Liu