ADVANCED MATERIALS
·
2023
·Vol. 35
·期 15
·2210440
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IF 29.4
Xiaojing Chen,Qianyun Tang,Jinqiang Wang,Yan Zhou,Fengqin Li,Yuexia Xie,Xingang Wang,Ling Du,Junru Li,Jun Pu,Quanyin Hu,Zhen Gu,Peifeng Liu
Immunotherapy has achieved revolutionary success in clinics, but it remains challenging for treating hepatocellular carcinoma (HCC) characterized by high vascularization. Here, it is reported that metal–organic framework-801 (MOF-801) can be employed as a stimulator of interferon genes (STING) through Toll-like receptor 4 (TLR4) not just as a drug delivery carrier. Notably, cytosine–phosphate–guanine oligodeoxynucleotides (CpG ODNs) and 5, 6-dimethylxanthenone-4-acetic acid (DMXAA) STING agonist with vascular disrupting function coordinates with MOF-801 to self-assemble into a nanoparticle (MOF-CpG-DMXAA) that effectively delivers CpG ODNs and DMXAA to cells for synergistically improving the tumor microenvironment by reprogramming tumor-associated macrophages (TAMs), promoting dendritic cells (DCs) maturation, as well as destroying tumor blood vessels. In HCC-bearing mouse models, it is demonstrated that MOF-CpG-DMXAA triggers systemic immune activation and stimulates robust tumoricidal immunity, resulting in a superior immunotherapeutic efficiency in orthotopic and recurrent HCC.
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高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-16
·
IF 12.6
Chu Hongyu,Xu Yajun,Shan Yuezhan,Sun Mengmeng,Zhao Weidong,Fang Xuedong,Shen Na,Tang Zhaohui
The vascular-disrupting agent DMXAA (5,6-dimethylxanthone-4-acetic acid) exhibits potent anticancer activity by targeting tumor vasculature and activating immune responses via the cGAS-STING pathway. However, its clinical application is hindered by nonspecific targeting and significant cardiovascular toxicity. This study introduces a novel self-amplified tumor-targeting delivery system(P@NPPD)comprising azide-functionalized poly(ethylene glycol)- b -poly-[( N -2-hydroxyethyl)-aspartamide]-DMXAA (N 3 -PEG- b -PHEA-DMXAA, NPPD) conjugated to DBCO modified platelets. Among them, NPPD was synthesized by conjugating DMXAA to N 3 -PEG- b -poly-[( N -2-hydroxyethyl)-aspartamide] through esterification. This system enhances tumor-specific drug delivery while minimizing systemic toxicity. Leveraging the natural tumor-homing properties of platelets and the coagulation cascade, P@NPPD selectively targets exposed collagen at tumor sites, initiating a self-amplifying release of DMXAA. This approach achieved a 2.61-fold improvement in targeting efficiency and an 89.1% tumor suppression rate. In addition to improving drug accumulation at tumor sites, P@NPPD significantly activated local immune responses, enhancing therapeutic efficacy and safety. These findings underscore the potential of P@NPPD as a promising platform for cancer therapy. Graphical abstract
研究领域:
药理学
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肿瘤学
·
生物医学工程
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高影响因子
Science Advances
·
2020
·Vol. 6
·期 35
·
IF 13.117
Jingjing Liang,Huifang Wang,Wenxiu Ding,Jianxiang Huang,Xuefei Zhou,Huiyang Wang,Xue Dong,Guangyao Li,Enguo Chen,Fei Zhou,Hongjie Fan,Jingya Xia,Bo Shen,Da Cai,Pengxun Lan,Hanliang Jiang,Jun Ling,Zhen Cheng,Xiangrui Liu,Jihong Sun
Mounting evidence suggests that immunotherapies are a promising new class of anticancer therapies. However, the immunosuppressive tumor microenvironment (TME), poor immunogenicity, and off-target toxicity hinder the broader implementation of immunotherapies. Here, we describe a novel strategy combining chemotherapy and immunotherapy to modulate the TME by systemically and concurrently delivering the chemotherapeutic agent SN38 (7-ethyl-10-hydroxycamptothecin) and the STING agonist DMXAA (5,6-dimethylxanthenone-4-acetic acid) into tumors using triblock copolymer nanoparticles, named PS3D1@DMXAA, which enhances antigen cross-presentation and induces the conversion of the immunosuppressive TME to immunogenic TME through the newly found synergistic function between SN38 and STING activation. PS3D1@DMXAA thus shows potent therapeutic efficacy in three mice tumor models and elicits remarkable therapeutic benefit when combined with anti–PD-1 therapy. Our engineered nanosystem offers a rational design of an effective immunotherapy combination regimen to convert uninflamed “cold” tumors into “hot” tumors, addressing the major challenges immunotherapies faced.
研究领域:
肿瘤学
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免疫疗法
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纳米技术
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癌症研究
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PubMed
高影响因子
Small
·
2017
·Vol. 13
·期 12
·1600954
·
IF 8.643
Shixian Lv,Zhaohui Tang,Wantong Song,Dawei Zhang,Mingqiang Li,Huaiyu Liu,Jianjun Cheng,Wu Zhong,Xuesi Chen
Nanomedicine (NM) cannot penetrate deeply into solid tumors, which is partly attributed to the heterogeneous microenvironment and high interstitial fluid pressure of solid tumors. To improve NM efficacy, there has been tremendous effort developing tumor-penetrating NMs by miniaturizing NM sizes or controlling NM surface properties. But progress along the direction of developing tumor penetrating nanoparticle has been slow and improvement of the overall antitumor efficacy has been limited. Herein, a novel strategy of inhibiting solid tumor with high efficiency by dual-functional, nontumor-penetrating NM is demonstrated. The intended NM contains 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a vascular-disrupting agent, and doxorubicin (DOX), a cytotoxic drug. Upon arriving at the target tumor site, sustained release of DMXAA from NMs results in disruption of tumor vessel functions, greatly inhibiting the interior tumor cells by cutting off nutritional supply. Meanwhile, the released DOX kills the residual cells at the tumor exterior regions. The in vivo studies demonstrate that this dual-functional, nontumor penetrating NM exhibits superior anticancer activity, revealing an alternative strategy of effective tumor growth inhibition.
研究领域:
药理学
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肿瘤学
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纳米技术
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癌症治疗
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Communications Biology
·
2024
·Vol. 7
·期 1
·1-11
·
IF 5.2
Qin Danhui,Song Hui,Wang Caiwei,Ma Xiaojie,Fu Yu,Zhao Chunyuan,Zhao Wei,Zhang Lei,Zhang Weifang
Stimulator of interferon genes (STING) is vital in the cytosolic DNA-sensing process and critical for initiating the innate immune response, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases. Zinc finger CCCH-type antiviral protein 1 (ZC3HAV1) specifically binds the CpG dinucleotides in the viral RNAs of multiple viruses and promotes their degradation. ZAPS (ZC3HAV1 short isoform) is a potent stimulator of retinoid acid-inducible gene I (RIG-I) signaling during the antiviral response. However, how ZC3HAV1 controls STING signaling is unclear. Here, we show that ZC3HAV1 specifically potentiates STING activation by associating with STING to promote its oligomerization and translocation from the endoplasmic reticulum (ER) to the Golgi, which facilitates activation of IRF3 and NF-κB pathway. Accordingly, Zc3hav1 deficiency protects mice against herpes simplex virus-1 (HSV-1) infection- or 5,6-dimethylxanthenone-4-acetic acid (DMXAA)-induced inflammation in a STING-dependent manner. These results indicate that ZC3HAV1 is a key regulator of STING signaling, which suggests its possible use as a therapeutic target for STING-dependent inflammation.
研究领域:
免疫学
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病毒学
·
炎症性疾病
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PubMed
高影响因子
BIOMACROMOLECULES
·
2023
·
IF 6.2
Cunguo Chen,Murong Hu,Yunyun Cao,Binbin Zhu,Jiashe Chen,Yashi Li,Junyi Shao,Sen Zhou,Pengfei Shan,Chen Zheng,Zhongyu Li,Zhiming Li
Cyclic dinucleotides (CDNs) are a promising class of immune agonists that trigger the stimulator of interferon genes (STING) to activate both innate and acquired immunity. However, the efficacy of CDNs is limited by drug delivery barriers. Therefore, we developed a combined immunotherapy strategy based on injectable reactive oxygen species (ROS)-responsive hydrogels, which sustainably release 5,6-dimethylxanthenone-4-acetic acid (DMXAA) as known as a STING agonist and indocyanine green (ICG) by utilizing a high level of ROS in the tumor microenvironment (TME). The STING agonist combined with photothermal therapy (PTT) can improve the biological efficacy of DMXAA, transform the immunosuppressive TME into an immunogenic and tumoricidal microenvironment, and completely kill tumor cells. In addition, this bioreactive gel can effectively leverage local ROS to facilitate the release of immunotherapy drugs, thereby enhancing the efficacy of combination therapy, improving the TME, inhibiting tumor growth, inducing memory immunity, and protecting against tumor rechallenge.
研究领域:
癌症免疫治疗
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药物递送系统
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生物医学工程
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药学
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肿瘤微环境
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2023
·
IF 10.8
Yuan-Fu Ding,Ziyi Wang,Cheryl H.T. Kwong,Yonghua Zhao,Greta S.P. Mok,Hua-Zhong Yu,Ruibing Wang
Camptothecin (CPT) and cisplatin (Pt) have shown synergistic effects on a variety of cancers during preclinical and clinical studies. However, the ratio of the two drugs often could not be precisely regulated in different delivery systems, which hinders the desired synergistic effect. In addition, the low delivery efficiency of the two drugs to the tumor further impedes the ideal therapeutic outcomes. Herein, we report that a platelet-mimicking supramolecular nanomedicine (SN) could precisely control of the ratio of CPT and Pt with a high tumor accumulation rate for cascade amplification of synergistic chemotherapy. The SN was fabricated via the host–guest interaction between cucurbit[7]uril conjugated hyaluronic acid (HA-CB[7]) and adamantane (ADA) respectively functionalized CPT- and Pt-based prodrugs . The ratio of CPT and Pt in the SN could be facilely regulated by simply controlling the loading ratio, based on the strong binding affinity between CB[7] and ADA, and SN60 with 60% CPT and 40% Pt showed the highest synergistic effects on 4T1 cells. To improve the tumor accumulation efficiency of SN, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a tumor vasculature-disruptive agent) was loaded into the optimized SN and then coated with platelet membrane to yield platelet-mimicking supramolecular nanomedicine ( [email protected] ). [email protected] could first passively accumulate in tumors owing to the enhanced permeability and retention (EPR) effect after intravenous administration. The initially release of DMXAA from [email protected] could induce tumor vascular disruption, and the resultant epithelial collagen exposure around the disrupted tumor vasculature provided a target for further recruitment of platelet-mimicking SN, leading to cascade amplification of tumor accumulation with synergistic chemotherapy. Hence, this platelet-mimicking supramolecular nanomedicine presents a universal supramolecular strategy to finely regulate the ratio of loaded pro-drugs, and improve the accumulation efficiency to amplify chemotherapy via platelet-mimics.
研究领域:
纳米医学
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药学
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肿瘤学
·
药物递送系统
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高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Yanmei Li,Junmei Nie,Xinyu Li,Ni Yan,Renjiang Kong,Jiaqi Huang,Yeyang Wu,Zhuofeng Li,Yingtao Zhong,Xin Chen,Hong Cheng
Stimulator of interferon genes (STING) plays an essential role in initiating the innate anti-tumor immunity, which could be activated by the cytosolic DNA but suppressed by the immunosuppressive cells. In this work, a self-delivery ternary immunostimulant (designated as ImmSt) is fabricated for colorectal cancer therapy with the immunological cascades of photodynamic DNA damage and T regulatory cell inhibition. Among which, the photosensitizer of Chlorin e6 (Ce6), the STING agonist of 5,6-dimethylxanthine-4-acetic acid (DMXAA) and the phosphatidylinositol 3-kinases (PI3Ks) inhibitor of ZSTK474 could self-assemble into uniform nanomedicine without drug excipient, which enhances the drug stability, bioavailability and pharmacological activities. Importantly, the photodynamic therapy (PDT) effect of ImmSt produces enormous reactive oxygen species to ablate tumor cells, and also triggers the release of cytosolic DNA to amplify the STING signal in combination with the STING agonist. Moreover, ImmSt is able to induce a systemic anti-tumor immunity by the cascade activation of T cells and the decrease of T regulatory cells. In vitro and in vivo results confirm that ImmSt can efficiently eradicate colorectal cancer without severe side effects, which may provide a sophisticated mechanism for immunotherapy in consideration of the immune activation and immunosuppressive factors.
研究领域:
肿瘤学
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免疫疗法
·
药理学
·
纳米技术
·
分子生物学
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