Materials Today Bio
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2025
·
IF 10.2
Su Li,Qinghua Wang,Chen Su,Zhen Jia,Guoshuang Shen,Mengting Da,Rui Yang,Jiuda Zhao,Daozhen Chen
Emerging nanodrug delivery strategies seek to overcome tumor heterogeneity and enhance drug penetration in the dense matrix of solid tumors. This study presents a dual-responsive nanoplatform, poly(lactic-co-glycolic acid)-disulfide-polyethylene glycol-glutamate (PLGA-SS-PEG-Glu) loaded with Gambogic acid (GA), engineered to exploit γ-glutamyltranspeptidase (GGT) and glutathione (GSH) triggers specific to the triple-negative breast cancer (TNBC) microenvironment. Designed with Boc-L-Glutamic Acid-1-tert-butyl ester (Boc-Glu-OtBu), this nanoplatform achieves enzyme-triggered charge reversal to enhance tumor penetration, facilitating GGT-induced charge-switching and GSH-responsive GA release. In vitro, PLGA-SS-PEG-Glu@GA shows potent cytotoxicity (IC 50 = 0.80 μg/ml) against 4T1 TNBC cells, inducing apoptosis and inhibiting cell proliferation through energy-dependent, GGT-mediated endocytosis. Compensatory Nrf2/HO-1 activation mechanistically induced by GA-loaded nanoplatform ultimately potentiated mitochondrial apoptotic pathway (Bcl-2/caspase-3) initiation, promoting apoptosis. In vivo, this nanoplatform leveraged its tumor-specific enzymatic and redox microenvironment-responsive properties to achieve enhanced deep intratumoral penetration. Treatment for 2 weeks effectively suppressed primary tumor growth, while extended therapy to one month significantly inhibited the formation of pulmonary metastatic foci. This dual-responsive strategy not only elevates drug bioavailability at the tumor site but also provides a promising solution to overcome critical barriers in solid tumor drug delivery.
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Frontiers in Bioengineering and Biotechnology
·
2021
·
IF 5.89
Wang Feng,Dong Lei,Wei Xixi,Wang Yongling,Chang Liansheng,Wu Hongwei,Liu Shuyuan,Chang Yuqiao,Yin Yaling,Luo Xiaoqiu,Jia Xiaojian,Yan Fei,Li Nana
Gambogic acid (GA) is a highly effective antitumor agent, and it is used for the treatment of a wide range of cancers. It is challenging to deliver drugs to the central nervous system due to the inability of GA to cross the blood–brain barrier (BBB). Studies have shown that ultrasound-targeted microbubble destruction can be used for transient and reversible BBB disruption, significantly facilitating intracerebral drug delivery. We first prepared GA–loaded porous-lipid microbubbles (GA porous-lipid/PLGA MBs), and an in vitro BBB model was established. The cell viability was detected by CCK-8 assay and flow cytometry. The results indicate that U251 human glioma cells were killed by focused ultrasound (FUS) combined with GA/PLGA microbubbles. FUS combined with GA/PLGA microbubbles was capable of locally and transiently enhancing the permeability of BBB under certain conditions. This conformational change allows the release of GA to extracellular space. This study provides novel targets for the treatment of glioma.
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CHEMICAL ENGINEERING JOURNAL
·
2020
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IF 10.652
Biao-Qi Chen,Ranjith Kumar Kankala,Yang Zhang,Shu-Ting Xiang,Han-Xiao Tang,Qi Wang,Da-Yun Yang,Shi-Bin Wang,Yu Shrike Zhang,Gang Liu,Ai-Zheng Chen
In an attempt to attain synergistic therapeutic benefits and address various intrinsic limitations of the highly efficient black phosphorus quantum dots (BPQDs), we fabricated poly( L -lactide)-poly(ethylene glycol)-poly( L -lactide) triblock copolymer (PLLA-PEG-PLLA)-based nanocomposites co-loaded with BPQDs and gambogic acid (GA) using the supercritical carbon dioxide (SC-CO 2 ) technology to achieve photoacoustic (PA) imaging-guided synergistic chemo-photothermal therapy. On the one hand, BPQDs displayed near-infrared (NIR)-induced hyperthermia through the high photothermal conversion efficiency. On the other hand, the NIR-responsive release of GA facilitated early apoptosis through specific binding to stress-induced overexpression of heat shock protein (HSP)-90 for combating thermoresistant tumor cells. GA significantly promoted the photothermal therapy (PTT) efficiency by enhancing both early and late apoptosis of BPQDs. Moreover, the encapsulation of BPQDs in the polymer significantly improved their chemical as well as photothermal stabilities. Our findings suggested that these nanocomposites fabricated using the eco-friendly supercritical fluid (SCF) technology provided good protection to the biodegradable BPQDs, offering a great potential towards cancer ablation through augmented synergistic effects.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2018
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IF 3.862
Zhongcheng Ke,Lei Yang,Hao Wu,Zihao Li,Xiaobin Jia,Zhenghai Zhang
This study aimed to develop a novel type of multilayer micelle using protamine (PRM) and hyaluronic acid (HA) for the delivery of gambogic acid (GA). GA-loaded micelles (GA-M) were simply and rapidly prepared using lecithin/solutol HS15 using a film-dispersion method. PRM and HA were added in sequence to form layer-by-layer self-assembled micelles (HA-PRM-GA-M), in which particle size, zeta potential , particle morphology, drug loading, encapsulation efficiency, and in vitro release were investigated. Surface charge reversal demonstrated that rapid HA detachment exposed PRM, leading to activation of a “proton sponge” effect in the hyaluronidase (HAase)-rich tumor microenvironment . Compared with coumarin 6-loaded micelles (C6-M), more efficient intracellular trafficking was observed for HA-PRM-C6-M, which is associated with the endosomal/lysosomal escaping ability of the exposed PRM. In vivo imaging showed increased enrichment of near infrared fluorescent dye (DIR)-loaded HA-PRM-DIR-M at the tumor site, suggesting that HA enhanced the active tumor targeting of GA. Furthermore, HA-PRM-GA-M showed the stronger antitumor activity than GA and GA-M against human lung adenocarcinoma (A549) tumor xenografts in nude mice . In summary, our findings show the potential of HA-PRM-GA-M as a novel intravenous drug carrier for the treatment of lung cancer.
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JOURNAL OF CONTROLLED RELEASE
·
2020
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IF 7.727
Xin Xu,Kunpeng Liu,Binbin Jiao,Kejun Luo,Jian Ren,Guan Zhang,Qingsong Yu,Zhihua Gan
Chemotherapy is the standard of care for bladder cancer after transurethral resection of the tumor. However, the rapid excretion of clinically used formulations of anticancer drugs make the common intravesical instillation chemotherapy far from efficient. Therefore, improving the muco-adhesion and penetrability of chemotherapeutic drugs became the key factors in the post-surgery treatment of superficial bladder cancers. Here, a reduction sensitive vehicle was developed to deliver the reactive oxygen species activated prodrug of gambogic acid for treatment of orthotopic bladder cancer. The positively charged chitosan can significantly enhance the adhesion and permeability of prodrug within the bladder wall. Moreover, by utilizing the different glutathione and ROS level between cancer cells and normal cells, the dual responsive nanoparticle can selectively and rapidly deliver drug in bladder cancer cells, and thus can significantly inhibit the proliferation of bladder cancer cells in an orthotopic superficial bladder cancer model without causing damage to normal cells. This work demonstrates that the smart prodrug nanomedicine may act as a promising drug-delivery system for local chemotherapy of bladder cancer with unprecedented clinical benefits.
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JOURNAL OF PHARMACEUTICAL SCIENCES
·
2020
·
IF 2.997
Ding Zhang,Wei Wang,Tao Hou,Yanjun Pang,Chao Wang,Shuai Wu,Qing Wang
Cutaneous melanoma is the deadliest form of skin cancer, and gambogic acid (GA) exhibits potent anti-melanoma activity. However, clinical application of GA via intravenous injection and oral administration is limited by systemic toxicity and rapid metabolism in the blood. Here, we developed a new, topical route of GA delivery for anti-melanoma activity and reduction of systemic toxicity. The results indicated that the barrier of the stratum corneum (SC) and low diffusion of GA in the hydrophilic viable skin (epidermis and dermis) limited the GA penetration through intact skin. The combination of azone (AZ) and propylene glycol (PG) showed obvious synergistic effects on skin penetration by GA via improving the permeability of the SC and greatly increasing the skin accumulation of GA, thereby forming a high drug concentration in the skin and achieving a topical targeted treatment of melanoma . In addition, GA (AZ–PG) achieved the same anti-melanoma effect via topical delivery as via intravenous injection. Intravenous injection and oral administration of GA induced remarkable pathological changes in various organs in mice, whereas GA was not toxic to various organs or to the skin via topical delivery. These findings indicated that topical administration of GA is an alternative route for melanoma treatment.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2022
·Vol. 20
·期 1
·1-22
·
IF 9.429
Li Rong-Tian,Zhu Yi-Dan,Li Wen-Ya,Hou Ying-Ke,Zou Yi-Ming,Zhao Ying-Hua,Zou Quan,Zhang Wen-Hua,Chen Jin-Xiang
A multifunctional nanoplatform with core–shell structure was constructed in one-pot for the synergistic photothermal, photodynamic, and chemotherapy against breast cancer. In the presence of gambogic acid (GA) as the heat-shock protein 90 (HSP90) inhibitor and the gold nanostars (AuNS) as the photothermal reagent, the assembly of Zr4+ with tetrakis (4-carboxyphenyl) porphyrin (TCPP) gave rise to the nanocomposite AuNS@ZrTCPP-GA (AZG), which in turn, further coated with PEGylated liposome (LP) to enhance the stability and biocompatibility, and consequently the antitumor effect of the particle. Upon cellular uptake, the nanoscale metal − organic framework (NMOF) of ZrTCPP in the resulted AuNS@ZrTCPP-GA@LP (AZGL) could be slowly degraded in the weak acidic tumor microenvironment to release AuNS, Zr4+, TCPP, and GA to exert the synergistic treatment of tumors via the combination of AuNS-mediated mild photothermal therapy (PTT) and TCPP-mediated photodynamic therapy (PDT). The introduction of GA serves to reduce the thermal resistance of the cell to re-sensitize PTT and the constructed nanoplatform demonstrated remarkable anti-tumor activity in vitro and in vivo. Our work highlights a facile strategy to prepare a pH-dissociable nanoplatform for the effective synergistic treatment of breast cancer.Graphical Abstract
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EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2021
·
IF 4.384
Ding Zhang,Boqi Chen,Qingke Mu,Wei Wang,Kaili Liang,Liyan Wang,Qing Wang
Anti-cutaneous melanoma activity of the skin-delivered gambogic acid (GA) has been reported in our previous study. However, it is difficult for GA to diffuse passively through intact skin without any enhancement means. In this study, a combination of chemical enhancers (EN: azone and propylene glycol) and physical ultrasound (US) was used to improve the percutaneous permeation of GA and enhance the anti-melanoma activity. The enhancement effect of the combination of EN and US (EN-US) on GA in vitro and in vivo was studied, and the enhancement mechanism and skin irritation were also evaluated. We showed that the parameters of US application at a constant frequency (30 kHz) with a duty cycle of 100% and intensity of 1.75 W/cm 2 for 20 min were optimal. In vitro , EN-US showed a considerable enhancement of the permeation of GA, and the enhancement effect was stronger than that with the use of EN or US alone. In vivo antitumor study showed that the tumor growth was significantly inhibited after percutaneous administration of GA by EN-US, more than in the intravenous injection group. The penetration enhancement mechanism revealed that EN-US not only altered the structure of lipid bilayers and keratins to reduce the barrier effect of the stratum corneum but also produced diffusion channels in the skin under the cavitation effect of US, thereby promoting the skin penetration of GA. In addition, there was no observable skin irritation in mice after treatment with EN-US. Our study demonstrated that the combination of EN and US improved the skin permeation and retention of GA to enhance the anti-melanoma activity. This method also provides technical guidance for the future development of topical and transdermal therapeutic system of GA.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·
IF 12.6
Menghui Liu,Yang Qiao,Sheng Cheng,Ziqing Su,Ziyi Li,Peng Gao,Xianwen Wang,Qiang Cai,Xingliang Dai
Background: Postoperative chemotherapy is essential for glioma treatment but faces two major limitations: the blood-brain barrier (BBB) restricts drug delivery, and tumor chemoresistance reduces therapeutic efficacy. To circumvent these hurdles, we engineered a 3D-bioprinted, sustained-release microneedle patches (MNs@GFD) that can be affixed directly to the postoperative tumor cavity, thereby bypassing the BBB and providing localized, long-term drug delivery. The patch incorporates gambogic acid-iron-doxorubicin nanozymes (GAFe@DOX, GFD) that simultaneously remodel the hypoxic tumor microenvironment via multi-enzyme activity and prime tumor cells for doxorubicin (DOX) cytotoxicity through ferroptosis. Results: Comprehensive characterization confirmed successful construction of MNs@GFD and demonstrated potent catalase-, peroxidase- and oxidase-like activities that alleviated intratumoral hypoxia. Multi-omics profiling revealed that GFD orchestrates a transcriptional program that robustly up-regulated pro-ferroptosis genes (ACSL4, COX2) while suppressing anti-ferroptosis guardians (GPX4, FTH1), leading to iron-dependent lipid peroxidation, mitochondrial collapse and concomitant apoptosis. Correspondingly, in vitro assays showed rapid and extensive death of glioma cells exposed to GFD, and in vivo studies in a post-surgical orthotopic model demonstrated that MNs@GFD markedly hindered tumor regrowth without systemic toxicity. Conclusion: MNs@GFD integrates localized drug release, BBB bypass, hypoxia relief and ferroptosis-mediated chemosensitization into a single platform, establishing a powerful and clinically translatable postoperative chemotherapeutic strategy against glioma.
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RSC Advances
·
2025
·Vol. 15
·期 15
·11283-11292
·
IF 4.6
Zixin Liang,Xinyi Xu,Ning Wang,Xintao He,Xingzhi Han,Liuqi Sang,Jing Hu,Xiaoping Qian
Colorectal cancer (CRC) remains a major global health challenge, particularly in advanced stages where drug resistance leads to high recurrence rates and poor survival outcomes. This study investigates a novel therapeutic approach combining gambogic acid (GA) with manganese dioxide (MnO2) nanoparticles (MBG NPs) to enhance anti-tumor efficacy in the acidic and hypoxic tumor microenvironment (TME). The development of MBG NPs involved conjugating MnO2 nanosheets with bovine serum albumin (BSA) for effective GA encapsulation, optimizing the delivery of both components. We explored the potential of Mn2+ ions released from MnO2 to synergize with GA to alleviate tumor hypoxia and modulate the TME, thereby improving immune response. In vitro assays demonstrated significant cytotoxicity of MBG NPs against mouse colon cancer cells (CT26 cells), with enhanced apoptosis and elevated reactive oxygen species (ROS) levels. In vivo studies using BALB/c mice showed that treatment with MBG NPs significantly reduced tumor volumes and improved survival rates compared to controls. Additionally, MBG NPs combined with programmed death-1 inhibitor (aPD-1) further augmented therapeutic effects. Histological analyses confirmed tumor necrosis and changes in TME composition, indicating the potential of this synergistic strategy to overcome drug resistance in microsatellite stable (MSS) CRC, inhibit tumor growth and benefit patient survival. These findings highlight the promising application of nanoparticle-based platforms in enhancing immunotherapy outcomes for advanced colorectal cancer.
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Nanomedicine
·
2026
·
IF 4.6
Shuzhen Hu,Su Shao
Aims Breast cancer (BC) remains the most prevalent malignancy in women, with conventional chemotherapy limited by drug resistance. This study develops a glutathione (GSH)-responsive nanoplatform combining chemotherapy with phototherapy against drug-resistant BC.Methods Gambogic acid (GA) was conjugated to carboxymethyl chitosan via disulfide bonds (GA-SS-CMCS, GSC), then loaded with graphene quantum dots (GQDs) to form GSC@GQD nanocomposites. The formulation was characterized by TEM, DLS, and NMR; photothermal performance, drug release, ROS generation, hemocompatibility, and anti-tumor efficacy were evaluated in MCF-7, MCF-7/ADR cells and MCF-7/ADR xenografts.Results GSC@GQD showed uniform morphology (~180 nm), GSH-triggered GA release (94% at 48 h), and hemolysis <5%. Under 808 nm irradiation, GSC@GQD raised temperature by 20 °C (vs. 9 °C for free GQDs), induced intracellular ROS accumulation, and achieved apoptosis rates of 86% (MCF-7) and 76% (MCF-7/ADR). In vivo, GSC@GQD + NIR suppressed tumor growth with satisfactory biosafety.Conclusions GSC@GQD integrates chemotherapy, photodynamic and photothermal therapy into a GSH-responsive platform, offering a promising strategy against drug-resistant BC.
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CELL STRESS & CHAPERONES
·
2020
·Vol. 26
·期 2
·367-375
·
IF 2.892
Chen Jun,Li Lihua,Zhou Yun,Zhang Jiahua,Chen Lei
Diabetic retinopathy (DR) is a serious microvascular complication of diabetes. Gambogic acid has been reported to have anti-inflammatory effect. However, the effect of GA on inflammatory response of ARPE-19 cells remains unclear. In our study, ARPE-19 cells were stimulated by palmitic acid (PA) induction in the presence of 30 mM glucose and then treated with 0.5, 1, 2, 5, 10, or 20 μM GA. CCK-8 assay showed that cell viability was increased by GA treatment at doses of 0.5, 1, and 2 μM instead of higher doses. ELISA analysis found that GA dose-dependently reduced the production of pro-inflammatory mediators TNF-α and IL-1β. Western blot indicated that GA downregulated the expression of NLRP3 inflammasome components including TXNIP, NLRP3, ASC, cleaved-caspase-1, and cleaved-IL-1β in a dose-dependent manner. In addition, Western blot and immunofluorescence analysis suggested that GA effectively increased the protein level of nuclear factor E2-related factor-2 (Nrf2). RT-qPCR showed that GA significantly increased the mRNA levels of Heme oxygenase-1 (HO-1) and NADPH:quinone oxidoreductase1 (NQO1). Furthermore, Nrf2 siRNA transfection confirmed the above effects of GA. In total, subtoxic doses of GA significantly flattened the inflammatory response induced by HG and PA in ARPE-19 cells via modulating the Nrf2 signaling pathway.
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