INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2017
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IF 3.649
Yingqi Xu,Shengpeng Wang,Hon Fai Chan,Yuling Liu,Hui Li,Chengwei He,Zeyong Li,Meiwan Chen
Mitochondria are important targets for the intracellular delivery of drugs and DNA. For mitochondria-targeted delivery, a mitochondriotropic molecule, triphenylphosphonium (TPP), was applied to the synthesis of amphiphilic TPP-poly(ethylene glycol)-poly(ε-caprolactone) (TPP-PEG-PCL) polymers. The TPP-PEG-PCL polymer was used to prepare micelles using a solvent evaporation method for the delivery of gambogic acid (GA) (GA-TPP). The micelles were obtained with a favorable particle size of 150.07 ± 11.71 nm and an encapsulation efficiency of 80.78 ± 1.36%, and they displayed homogeneous spherical shapes. The GA-TPP micelles exerted enhanced cytotoxic and pro-apoptotic effect against A549 cells compared to free GA and GA-loaded PEG-PCL (GA-PP) micelles, due to the inhibition of the expression of apoptosis-related proteins and promotion of caspase 3/7 and caspase 9 activity. Notably, the mitochondria-targeting GA-TPP micelles selectively accumulated in the mitochondria, inducing the loss of mitochondrial membrane potential and the release of cytochrome c , thereby achieving improved mitochondria-targeting effects. In conclusion, the GA-TPP micelle system shows great promise for lung cancer treatment by inducing an apoptotic effect via the mitochondrial signaling pathway.
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Current Drug Delivery
·
2022
·Vol. 19
·期 4
·491-507
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IF 3.758
Zhao Xinghua,Ding Shi,Li Shengnan,Wang Yang,Jiang Mingjun,Liu Ju,Chen Ye
Aim: An active-passive dual-targeting gambogic acid HPMA Copolymer Coupling drug system with high efficiency, low toxicity and high selectivity was constructed. Methods: The gambogic acid HPMA copolymer coupling drug system was constructed and its structure was characterized. The
cytotoxicity of gambogic acid HPMA copolymer was detected by MTT assay. The pharmacokinetics of gambogic acid HPMA copolymer was evaluated in mice. Targetability of gambogic acid HPMA copolymer was evaluated by tissue distribution experiment. The in vitro antitumor activity of gambogic acid
HPMA copolymer was evaluated by pharmacodynamics experiment in mice. Results: Two copolymers of gambogic acid HPMA were successfully prepared. The copolymers showed reduced cytotoxicity and a certain sustained release effect and targeting property. In vivo pharmacodynamic experiments
also showed better anti-tumor effects than GA. Discussion: In this study, gambogic acid was combined with HPMA polymer and the targeting molecule D-galactose/folic acid to form a polymer micelle with high efficiency, low toxicity and high selectivity for active-passive dual targeting.
The construction of the drug system provides new ideas for future formulation research and development.
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Advanced Healthcare Materials
·
2024
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IF 10
Ruyi Wang,Yuxiao Xiao,Zhongtao Zhang,Xiaoxian Huang,Wanfang Zhu,Xiao Ma,Feng Feng,Wenyuan Liu,Lingfei Han,Wei Qu
Poor in vivo characteristics of gambogic acid (GA) and difficulties in industrial manufacturing of its nanocarriers have hindered its clinical translation. Therefore, a reproducible nano-drug delivery system must be developed to realize simpler manufacture and address inherent defects of GA, such as short circulation and severe side effects, in order to facilitate its clinical application. Herein, a drug self-assembled nanoparticles (NPs) consisting of a hydrophobic prodrug based on GA and oleyl alcohol (OA), as well as vitamin E-polyethylene glycol succinate (TPGS) as a shield to improve the stability of the NPs is reported. The preparation method is simple enough to stably facilitate large-scale manufacturing. The self-assembled NPs exhibit a remarkably high drug-loading capacity, and their prolonged circulation enables the NPs to demonstrate superior antitumor efficacy in both cellular and animal models. The flexible hydrophobic long chain wraps GA groups, which mitigates vascular irritation and reduces hemolysis rates. Consequently, the prodrug nano-system addresses GA-related concerns regarding stability, efficacy, and safety, offering a simple, stable, and secure nano-platform for similar candidate drugs.
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Advanced Therapeutics
·
2022
·Vol. 6
·期 1
·2200201
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IF 5.003
Shanshan Liu,Jianfeng Wang,Haiguang Li,Chen Xu,Yimin Guo,Xiaotong Bao,Shaokang Guan,Hairong Liu,Tao Zhang
Chemotherapy combined with nanocarriers has received increased attention as a thriving strategy for tumor therapy. However, drug resistance (DR), poor circulation, and retention in cells are the main challenges of this therapy. Herein, a novel strategy is developed to target drug delivery via π–π stacking interactions to overcome DR and short circulation and retention in cells. Carbon quantum dots (CDs) and gambogic acid (GA) are assembled via a π–π stacking interaction, which increases the drug-loading capacity of CDs as well as the circulation and retention of GA-loaded CDs (CDs/GA). CDs/GA significantly inhibit cell proliferation because CDs enter the nucleus and avoid drug pump recognition. GA released from CDs/GA promotes apoptosis by inducing the production of reactive oxygen species via the mitochondrial pathway. As a result, the delivery system of CDs/GA via π–π stacking displays a significant therapeutic effect on hepatoma (HepG2) and cervical cancer (HeLa) cells. The mechanisms of DR and induction of apoptosis are further investigated. The results suggest that chemotherapy combined with CDs can facilitate the targeting of the nucleus, thereby inducing apoptosis via the mitochondrial pathway.
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JOURNAL OF SUPERCRITICAL FLUIDS
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2019
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IF 3.481
Shu-Ting Xiang,Biao-Qi Chen,Ranjith Kumar Kankala,Shi-Bin Wang,Ai-Zheng Chen
Despite the captivating interest for its potential anticancer efficacy against multiple types of cancer and ability to overcome multidrug resistance, the practical application of gambogic acid (GA) has been hampered by its poor water solubility. Herein, the fabrication of nanosized GA particles (251.2 nm ± 85.6 nm) using eco-friendly supercritical fluid (SCF)-assisted rapid expansion of a supercritical solution into a liquid solvent (RESOLV) process was demonstrated. The equilibrium solubility of GA in supercritical carbon dioxide (SC−CO 2 ) was initially determined at altered supercritical conditions (P: 10.0 MPa to 30.0 MPa, T: 308.15 K–328.15 K) and the obtained data points were then correlated using various density-based models including Méndez-Santiago and Teja, Bartle as well as Chrastil models. The solubility of GA in SC−CO 2 was found to be between 1.63 × 10 −6 and 22.62 × 10 −6 in terms of GA mole fraction, and considerably good correlation agreement was obtained with all the applied models and being the lowest deviations obtained with the Méndez-Santiago and Teja model. Furthermore, the fabricated GA nanoparticles (NPs) through benign RESOLV technique, were systematically characterized. Subsequently, in vitro antiproliferation tests resulted in its augmented antitumor efficacy due to enhanced solubility of GA. Together, the results have suggested that the benign RESOLV process has successfully fabricated nanosuspensions of GA with enhanced bioavailability and antineoplastic efficacy and may have great potential in pharmaceutics.
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BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Jiajian Wang,Lanqing Zhang,Runfang Li,Rui Yang,Fan Yang,Fei Yu,Jihong Zhang
TP53, the most frequently mutated gene in human cancers, undergoes a functional transformation from a tumor suppressor to an oncoprotein, thereby enhancing tumor aggressiveness, metastatic potential, and resistance to therapy. Given the prevalence of p53 mutations in cancer, the reactivation of wild-type p53 function presents a compelling therapeutic strategy for these malignancies. In this study, we identified gambogic acid (GA), a natural compound, as a potent reactivator of mutant p53 transcriptional activity. Immunofluorescence and co-immunoprecipitation assays revealed that GA treatment upregulates wild-type p53 expression while depleting mutant p53 in cancer cells. The time-dependent restoration of p53′s DNA-binding capacity and transcriptional regulatory activity by GA was further demonstrated through EMSA and ChIP. Consequently, GA robustly induced the expression levels of canonical p53 downstream target genes, confirming functional restoration of p53 signaling. In addition, GA synergizes with RSL3, a GPX4 inhibitor, to promote ferroptosis in mutant p53 cancer cells in both cellular and animal studies. In summary, our findings identify GA as a promising compound that reactivates mutant p53 through thiol modification, restoring its wild-type function and inducing ferroptosis in p53-mutant cancer cells. The findings of this study establish a foundational rationale and new perspectives for a mutant p53-directed therapeutic paradigm in oncology.
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Advanced Science
·
2026
·
IF 14.1
Tong Yang,Chong Qiu,Yulei Li,Ying Zhang,Chen Wang,Jie Zhou,Zheng Chu,Ang Ma,Ling Huang,Yin Kwan Wong,Junzhe Zhang,Peng Gao,Cui Liu,Junhua Zhang,Huan Tang,Jigang Wang
Triple-negative breast cancer (TNBC) is an aggressive subtype lacking targeted therapies due to the absence of hormone receptors and HER2 expression, resulting in poor clinical outcomes and limited treatment options. Identifying novel vulnerabilities is therefore critical to advancing TNBC therapeutics. Mitochondrial metabolism has emerged as a key regulator of cancer cell survival and proliferation, with serine hydroxymethyltransferase 2 (SHMT2) playing a central role in mitochondrial one-carbon metabolism by supplying one-carbon units for nucleotide biosynthesis and maintaining redox homeostasis. Despite its established importance in cancer metabolism, the functional role and therapeutic potential of SHMT2 in TNBC remain underexplored. Here, we demonstrate that gambogic acid (GA), a natural product with reported anticancer properties, exerts potent and selective cytotoxicity against TNBC cells by covalently targeting SHMT2. GA binds specifically to the critical cysteine residue Cys241, inhibiting SHMT2 enzymatic activity and disrupting mitochondrial function. This leads to bioenergetic collapse, activation of the Nrf2/HO-1 axis, iron overload, and induction of ferroptosis, a non-apoptotic form of cell death increasingly recognized for its therapeutic potential. Our integrative chemoproteomic and mechanistic studies reveal a novel SHMT2-mitochondria-Nrf2/HO-1-ferroptosis axis driving GA's anti-TNBC activity. Moreover, SHMT2 overexpression in TNBC correlates with tumor aggressiveness and poor prognosis, underscoring its role as a metabolic oncogene and promising drug target. These findings establish GA as a novel covalent SHMT2 inhibitor and provide a new framework for exploiting metabolic vulnerabilities to overcome TNBC treatment resistance.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·Vol. 23
·期 1
·1-23
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IF 12.6
Qiao Yang,Liu Menghui,Zhang Yiqun,Ni Fan,Yu Liangchen,Chen Zhao,Dai Xingliang,Wang Xianwen
The complex dual role of autophagy provides new insights for enhancing tumor treatment efficacy. However, effectively regulating this process is key to enhancing therapeutic efficacy. To address this challenge, this study designed a gambogic acid-iron nanozyme (GAFe) as a novel carrier to enhance the effectiveness of chemotherapy drugs such as doxorubicin (DOX) by inducing excessive autophagy and oxidative stress. The synthesized nanoparticle (GAFe@DOX) is capable of slowly releasing its active components over a prolonged period within tumor tissues. Gambogic acid can induce excessive autophagy, while the multi-enzyme activity of GAFe and the activation of ferroptosis amplify and sustain excessive autophagy, thereby enhancing the chemotherapy effect of DOX. Meanwhile, ferroptosis activated via the GPX4 pathway by GAFe can synergize with excessive autophagy, amplifying oxidative stress and consequently enhancing the overall therapeutic efficacy. Characterization experiments confirmed the successful synthesis of GAFe@DOX and probe assays demonstrated its superior multi-enzyme activity. In vitro cell studies showed that GAFe@DOX effectively kills tumor cells, while in vivo animal experiments revealed its excellent biocompatibility and significant tumor growth inhibition. This study demonstrates a promising strategy to improve tumor therapeutic efficacy by modulating excessive autophagy and oxidative stress. This provides a novel and effective approach to improve the treatment of refractory tumors such as glioblastoma. Graphical abstract
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International Journal of Nanomedicine
·
2023
·
IF 8
Dinghu Zhang,Yanhong Chu,Hanqing Qian,Lingyu Qian,Jie Shao,Qiuping Xu,Lixia Yu,Rutian Li,Quanan Zhang,Fenglei Wu,Baorui Liu,Qin Liu
Introduction Gambogic acid (GA) is proved to have anti-tumor effects on gastric cancer. Due to poor solubility, non-specific biological distribution, toxicity to normal tissues and short half-life, it is hard to be applied into the clinic. To overcome these issues, we developed a thermosensitive and injectable hydrogel composed of hydroxypropyl cellulose, silk fibroin and glycerol, with short gelling time, good compatibility and sustained release, and demonstrated that the hydrogel packaged with gambogic acid nanoparticles (GA-NPs) and tumor-penetrating peptide iRGD could improve the anti-tumor activity.Methods The Gelling time and micropore size of the hydrogels were regulated through different concentrations of glycerol. Controlled release characteristics of the hydrogels were evaluated with a real-time near-infrared fluorescence imaging system. Location of nanoparticles from different carriers was traced by confocal laser scanning microscopy. The in vivo antitumor activity of the hydrogels packaging GA-NPs and iRGD was evaluated by investigating tumor volume and tumor size.Results The thermo-sensitive properties of hydrogels were characterized by 3–4 min, 37°C, when glycerol concentration was 20%. The hydrogels physically packaged with GA-NPs and iRGD showed higher fluorescence intensity than other groups. The in vivo study indicated that the co-administration of GA-NPs and iRGD by hydrogels had higher antitumor activity than the GA-loaded hydrogels and free GA combining with iRGD. Free GA group showed few antitumor effects. Compared with the control group, the body weight in other groups had no obvious change, and the count of leukocytes and hemoglobin was slightly decreased.Discussion The hydrogel constructed iRGD and GA-NPs exerted an effective anti-tumor effect possibly due to retention effect, local administration and continuous sustained release of iRGD promoting the penetration of nanoparticles into a deep part of tumors. The delivery system showed little systemic toxicity and would provide a promising strategy to improve anti-gastric cancer efficacy.
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International Journal of Nanomedicine
·
2026
·
IF 8.7
Zhongcheng Ke,Tao Luo,Xiaoling Cheng,Xuwen Chai,Zitong Zhu,Zhusheng Huang,Zhen Wang
Purpose Gambogic acid (GA) shows potent inhibitory activity against various malignancies. However, achieving precise targeted delivery and spatiotemporal control of drug release at tumor sites remains a significant challenge. This study aimed to develop a hyaluronic acid (HA)-modified, redox-responsive drug delivery system based on a methoxy polyethylene glycol-linked GA prodrug (mPEG-ss-GA). Methods The amphiphilic prodrug, mPEG-ss-GA, was synthesized by conjugating GA to methoxy polyethylene glycol (mPEG) via a disulfide linkage. Subsequently, it spontaneously self-assembled with HA in an aqueous medium to form HA-modified mPEG-ss-GA micelles (HA/mPEG-ss-GA-M). The physicochemical properties of the micelles, including particle size, zeta potential, morphology, and in vitro release profiles, were systematically characterized. Cellular uptake in human non-small cell lung cancer cells (A549) was visualized using fluorescence microscopy. Furthermore, the in vitro pro-apoptotic effects were quantified using an Annexin V–propidium iodide (PI) binding assay. Finally, the in vivo anti-tumor efficacy was evaluated in a subcutaneous xenograft tumor model. Results The HA/mPEG-ss-GA-M micelles exhibited an average particle size of 251 nm with a zeta potential of −17.36 mV. The system demonstrated glutathione (GSH)-triggered drug release, with release kinetics that aligned well with the Higuchi model. In vitro studies revealed that HA/mPEG-ss-GA-M significantly enhanced cellular uptake, induced apoptosis, and suppressed cell migration. In vivo experiments showed that HA/mPEG-ss-GA-M achieved a tumor volume inhibition rate of 54.09%, compared to 29.56% for free GA. Conclusion HA/mPEG-ss-GA-M is a promising drug delivery system for targeted non-small cell lung cancer therapy and offers precise and efficient treatment options.
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JOURNAL OF MOLECULAR LIQUIDS
·
2022
·
IF 6.633
Ziling Chang,Yuxiang Yang,Bo Zhao,Huafei Li,Yuxia Guan,Yi Zhao,Hongming Yuan,Chaoying Ni
Hydrophilic mesoporous organosilica nanoparticles (HMNPs) were synthesized by introducing Fe 3 O 4 on the basis of mesoporous organosilicon nanoparticle hollow spheres as a drug carrier. N- and S- doped graphene quantum dots (NS-GQDs) and polyethylenimine (PEI) were grafted onto the surface of HMNPs. Finally, two types of composite mesoporous particles, HMNPs-NS-GQDs-PEI-HA and HMNPs-NS-GQDs-PEI-FA which can enter VX2 cells for fluorescence confocal imaging, were further modified by targeting ligand hyaluronic acid (HA) and folic acid (FA). The heteroatoms of NS-GQDs have intelligent functional effects, which can not only improve the photoluminescence performance of GQDs, but also generate conjugated quantum dots with GA, so as to synergistically improve the drug effectiveness. Under illumination by near-infrared (NIR) radiation, gambogic acid (GA)-loaded HMNPs was promoted to the sustained release of gambogic acid. The loading and sustained release of the anticancer drug GA on the compound mesoporous particles were studied. The cytotoxicity and antitumor properties of the compound mesoporous particles were investigated by both in vitro cell experiments and in vivo experiments in mice. The results showed that HMNPs-NS-GQDs-PEI-HA and HMNPs-NS-GQDs-PEI-FA have desired fluorescence and magnetic properties for cell fluorescence imaging and magnetic targeting of cancer cells. Both of composite mesoporous particles have desired loading capacity on GA and pH-responsive drug release behavior as well as low cytotoxicity and good biocompatibility. The cell survival rate of HMNPs-NS-GQDs-PEI-HA and HMNPs-NS-GQDs-PEI-FA loaded with GA was only 7.69% and 8.71%, respectively, after 24 h, which can effectively induce the apoptosis of VX2 cells. Tumor experiments in mice demonstrated that HMNPs-NS-GQDs-PEI-HA inhibits tumor growth and exhibits magnetic targeting function.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yuanhao Jing,Chun Wang,Chunhua Li,Zijian Wei,Dan Lei,Anni Chen,Xiang Li,Xiaowen He,Lanqi Cen,Mengna Sun,Baorui Liu,Bin Xue,Rutian Li
Gambogic acid is a natural compound with anticancer properties and is effective for many tumors. But its low water solubility and dose-dependent side effects limit its clinical application. This study aims to develop a novel drug delivery system for intratumoral delivery of gambogic acid. In our experimental study, we propose a new method for encapsulating gambogic acid nanoparticles using a manganese composite hyaluronic acid hydrogel as a carrier, designed for targeted drug delivery to tumors. The hydrogel delivery system is synthesized through the coordination of hyaluronic acid-dopamine (HA-DOPA) and manganese ions. The incorporation of manganese ions serves three purposes:1.To form cross-linked hydrogels, thereby improving the mechanical properties of HA-DOPA.2.To monitor the retention of hydrogels in vivo in real-time using magnetic resonance imaging (MRI).3.To activate the body's immune response. The experimental results show that the designed hydrogel has good biosafety, in vivo sustained release effect and imaging tracking ability. In the mouse CT26 model, the hydrogel drug-loaded group can better inhibit tumor growth. Further immunological analysis shows that the drug-loaded hydrogel group can stimulate the body's immune response, thereby better achieving anti-tumor effects. These findings indicate the potential of the developed manganese composite hyaluronic acid hydrogel as an effective and safe platform for intratumoral drug delivery. The amalgamation of biocompatibility , controlled drug release , and imaging prowess positions this system as a promising candidate for tumor treatment.
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