Materials Today Bio
·
2025
·
IF 10.2
Wenzhe Yuan,Xiaoli Jiang,Jiayang Qin,Shenglan Wang,Mengxue Liu,Jiayi Jin,Feng Geng,Xiaohong Pan,Jing Zhang
Combining immunotherapy with photodynamic therapy (PDT) can optimize their synergistic therapeutic efficacy against triple-negative breast cancer (TNBC), but the limited accumulation of photosensitizers at the tumor site and the off-target binding of PD-L1 antibody with hematopoietic cells and normal tissues severely reduce the therapeutic efficacy and increase the systemic toxicity, leading to failure in the clinical treatment. Therefore, engineered Escherichia coli Rosetta(DE3) expressing PD-L1 nanobody (Rosetta(pPD-L1nb)) are constructed and covalently conjugated with a photosensitizer, chlorin e6 (Ce6), to develop hybrid bacteria (CeRosetta(pPD-L1nb)). As a facultative anaerobe, CeRosetta(pPD-L1nb) can targetedly accumulate and colonize at the hypoxic and hypernutrient microenvironment of tumor, consistently synthesize PD-L1nb and compete for nutrition consumption with tumor cells to inhibit tumor growth. Under light irradiation, CeRosetta(pPD-L1nb) can not only generate reactive oxygen species (ROS) to directly eliminate tumor cells and induce the infiltration of immune cells into tumors and the immunogenic cell death (ICD) to activate adaptive immune responses, but also spatiotemporally release PD-L1nb due to the PDT-induced lysis in the tumor site to reverse the immunosuppressive tumor microenvironment and activate the systemic antitumor immune response, therefore exert synergistic antitumor effects of anti-PD-L1 therapy and PDT. Altogether, the hybrid bacteria CeRosetta(pPD-L1nb) can serve as an all-in-one strategy for optimizing the synergistic therapeutic efficacy in the combination therapy of TNBC.
研究领域:
肿瘤学
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生物医学工程
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药理学
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产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 18
·4375
·
IF 4.2
Ran Luo,Haoyi Zhao,Siqi Deng,Jiale Wu,Haijun Wang,Xiaoshan Guo,Cuicui Han,Wenkang Ren,Yinglong Han,Jianwen Zhou,Yu Lin,Ming Bu
In this study, novel ergosterol peroxide (EP) derivatives were synthesized and evaluated to assess their antiproliferative activity against four human cancer cell lines (A549, HepG2, MCF-7, and MDA-MB-231). Compound3gexhibited the most potent antiproliferative activity, with an IC50value of 3.20 µM against MDA-MB-231. This value was 5.4-fold higher than that of the parental EP. Bioassay optimization further identified3gas a novel glutaminase 1 (GLS1) inhibitor (IC50= 3.77 µM). In MDA-MB-231 cells,3greduced the cellular glutamate levels by blocking the glutamine hydrolysis pathway, which triggered reactive oxygen species production and induced caspase-dependent apoptosis. Molecular docking indicated that3ginteracts with the reaction site of the variable binding pocket by forming multiple interactions with GLS1. In a mouse model of breast cancer,3gshowed remarkable therapeutic effects at a dose of 50 mg/kg, with no apparent toxicity. Based on these results,3gcould be further evaluated as a novel GLS1 inhibitor for triple-negative breast cancer (TNBC) therapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症研究
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2023
·
IF 5.8
Kexin Zhang,Jiaxin Zhu,Ruyi Wang,Wanfang Zhu,Zhongtao Zhang,Liangping Gong,Feng Feng,Wenyuan Liu,Lingfei Han,Wei Qu
As the main systemic treatment for triple-negative breast cancer (TNBC), the bleak medical prognosis of chemotherapy resulted in impaired life quality by tumor recurrence and metastasis. The feasible cancer starvation therapy could inhibit tumor progression by blocking energy supplements, however, the mono-therapeutic modality showed limited curing efficacy due to heterogeneity and abnormal energy metabolism of TNBC. Thus, the development of a synergistic nano-therapeutic modality involving different anti-tumor mechanisms to simultaneously transport medicines to the organelle where metabolism took place, might remarkably improve curing efficacy, targeting ability, and bio-safety. Herein, the hybrid [email protected] NPs were prepared by doping multi-path energy inhibitors Berberine (BBR) and Lonidamine (LND) as well as the chemotherapeutic agent Gambogic acid (GA). Our research indicated that [email protected] NPs inherited the mitochondria targeting ability from BBR to accumulate precisely at the “energy factory” mitochondria, and then induce starvation therapy to efficiently eradicated cancer cells by coordinately powered off tumor cells via a “three-prone strategy” to cut off mitochondrial respiration, glycolysis, and glutamine metabolism. The inhibition of tumor proliferation and migration was enlarged by the synergistic combination with chemotherapy. Besides, apoptosis via mitochondria pathway and mitochondria fragmentation supported the hypothesis that NPs eliminated MDA-MB-231 cells by violently attacking MDA-MB-231 cells and especially the mitochondria. In summary, this synergistic chemo-co-starvation nanomedicine proposed an innovative site-specific targeting strategy for improved tumor treatment and decreased toxicity to normal tissues, which provided an option for clinical TNBC-sensitive treatment.
研究领域:
纳米技术
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肿瘤学
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
DALTON TRANSACTIONS
·
2022
·Vol. 51
·期 29
·10930-10942
·
IF 4.569
Yixuan Wu,Dandan Zhao,Jinting Shang,Wenxin Huang,Zhanfen Chen
Polynuclear platinum(II) complexes represent a class of great prospective Pt-based antitumor drugs that may expand the antitumor spectrum and overcome the clinical problems of drug resistance and side effects of platinum-based drugs. Herein, a novel star-shaped trinuclear platinum(II) complex [Pt3(L–3H)Cl3] (1, L = 2,4,6-tris[(2-hydroxybenzyl)(2-pyridylmethyl)amine]-1,3,5-triazine) and its monomer [Pt(L′–H)Cl] (2, L′ = (2-hydroxybenzyl)(2-pyridylmethyl)amine) were synthesized and characterized. The in vitro antiproliferative activities of complexes 1 and 2 against a panel of human cancer cell lines including MDA-MB-231 (triple-negative breast cancer, TNBC), MCF-7 (breast), HepG-2 (liver), and A549 (lung) were investigated. The results revealed that 1 exhibited much higher antiproliferative properties than its monomer 2 against the tested cell lines. Importantly, 1 possessed 3.3-fold higher antiproliferative activity as compared with cisplatin against the TNBC cell line MDA-MB-231. Another TNBC cell line MDA-MB-468 is also sensitive to 1. The results indicated that 1 might have the potential to act as a candidate for the treatment of TNBC. Cellular uptake and distribution studies showed that 1 could pass through the membrane of cells and enter into cells and mainly accumulate in the nuclei and mitochondria. 1 could bind to DNA in a cooperative groove-electrostatic-platinating binding mode and induce stronger DNA double-strand breaks (DSBs) and damaging effects on MDA-MB-231 than cisplatin (upregulation of γ-H2AX). Moreover, the DNA damage could not be easily repaired (upregulation of p53), which would exert a much positive influence on the overcoming of drug resistance. Additionally, flow cytometry studies showed that 1 arrested the cell cycle in the G0/G1 phase, induced mitochondrial membrane depolarization, increased ROS generation, and induced cell apoptosis. The results demonstrated that 1 could target simultaneously mitochondria and nuclei that gave rise to mitochondrial injury and DNA damage and ultimately efficiently promote the apoptotic death of tumor cells. Further mechanistic studies showed that 1 induced MDA-MB-231 cell apoptosis via the p53-mediated mitochondrial pathway by upregulating Bax and cytochrome c and downregulating Bcl-2 proteins, leading to the activation of caspase-3 and upregulation of the cleaved-PARP level. Taken together, 1 with such a synergic mechanism has great potential to be an effective anticancer agent that can overcome treatment resistance in TNBC.
研究领域:
癌症研究
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药物化学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Small
·
2023
·
IF 13.3
Chongzhi Wu,Fu Zhang,Bowen Li,Zhiyao Li,Xin Xie,Yong Huang,Zhuo Yao,Yuan Chen,Yuan Ping,Weidong Pan
Triple-negative breast cancer (TNBC) displays a highly aggressive nature that originates from a small subpopulation of TNBC stem cells (TNBCSCs), and these TNBCSCs give rise to chemoresistance, tumor metastasis, and recurrence. Unfortunately, traditional chemotherapy eradicates normal TNBC cells but fails to kill quiescent TNBCSCs. To explore a new strategy for eradicating TNBCSCs, a disulfide-mediated self-assembly nano-prodrug that can achieve the co-delivery of ferroptosis drug, differentiation-inducing agent, and chemotherapeutics for simultaneous TNBCSCs and TNBC treatment, is reported. In this nano-prodrug, the disulfide bond not only induces self-assembly behavior of different small molecular drug but also serves as a glutathione (GSH)-responsive trigger in controlled drug release. More importantly, the differentiation-inducing agent can transform TNBCSCs into normal TNBC cells, and this differentiation with chemotherapeutics provides an effective approach to indirectly eradicate TNBCSCs. In addition, ferroptosis therapy is essentially different from the apoptosis-induced cell death of differentiation or chemotherapeutic, which causes cell death to both TNBCSCs and normal TNBC cells. In different TNBC mouse models, this nano-prodrug significantly improves anti-tumor efficacy and effectively inhibits the tumor metastasis. This all-in-one strategy enables controlled drug release and reduces stemness-related drug resistance, enhancing the chemotherapeutic sensitivity in TNBC treatment.
研究领域:
肿瘤学
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药学
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纳米技术
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
DRUG DELIVERY
·
2017
·
IF 6.402
Wei Chen,Lin Li,Xiaofen Zhang,Yuan Liang,Zhijun Pu,Lingfeng Wang,Jingxin Mo
Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease with no approved targeted therapy. Curcumin has shown therapeutic potential against TNBC, but it shows low bioavailability and low efficacy when administered as a free drug. Here we describe a novel vehicle for in vivo delivery of curcumin based on the phosphorylated calixarene POCA4C6. Curcumin-loaded POCA4C6 micelles (CPM) were prepared using the thin-film method and they showed a unilamellar structure with an average particle size of 3.86 nm. The micelles showed high curcumin encapsulation efficiency and loading was based on liquid chromatography-tandem mass spectrometry. Studies with cell cultures suggest that CPM can sustainably release curcumin in a pH-dependent manner. The micelles efficiently inhibited proliferation, invasion, migration and tumor spheroid formation by BT-549 human breast cancer cells. These effects involved increased apoptosis and reduced levels of nuclear β-catenin and androgen receptor. After injection into tumor xenografts, CPM persisted in the tumor tissue and efficiently inhibited tumor growth without causing obvious systemic toxicity. CPM also significantly reduced levels of CD44+/CD133+ breast cancer stem cells. Our results highlight the potential of CPM as an effective therapy against TNBC.
研究领域:
肿瘤学
·
药剂学
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药物递送系统
·
癌症干细胞
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Taiyuan Liu,Xinghui Si,Liping Liu,Sheng Ma,Zichao Huang,Yu Zhang,Wantong Song,Yingchao Zhang,Xuesi Chen
Breast cancer is the most commonly diagnosed cancer, and surgical resection is the first choice for its treatment. With the development of operation techniques, surgical treatment for breast cancer is evolving toward minimally invasive and breast-conserving approaches. However, breast-conserving surgery is prone to an increased risk of cancer recurrence and is becoming a key challenge that needs to be solved. In this study, we introduce a one-shot injectable nano-in-gel vaccine (NIGel-Vax) for postoperative breast cancer therapy. The NIGel-Vax was constructed by mixing protein antigens with PEI-4BImi-Man adjuvant and then encapsulated in a hydrogel made with oxidized dextran (ODEX) and 4-arm PEG-ONH2. Using 4T1 tumor-extracted proteins as antigen, the NIGel-Vax achieved a 92% tumor suppression rate and a 33% cure rate as a postoperative therapy in the 4T1 tumor model. Using the tumor-associated antigen trophoblast cell-surface antigen 2 (TROP2) protein as the antigen, NIGel-Vax achieved a 96% tumor suppression rate and a 50% cure rate in triple-negative breast cancer (TNBC) models. This design provides an encouraging approach for breast cancer postoperative management.
研究领域:
肿瘤学
·
药理学
·
生物医学工程
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2024
·
IF 4.8
Shengsheng Mei,Shanshan Peng,Eu Gene Vong,Jinbiao Zhan
Background Clinical data indicate that a substantial portion of cancer patients, though eligible for immune checkpoint inhibitor (ICI) therapy, cannot fully benefit from ICI monotherapy due to the poor immunogenicity of tumors and lack of tumor-infiltrating lymphocytes within the ‘cold’ tumor microenvironment (TME). In addition to poor antibody penetrance into the TME, systemic delivery of ICIs is associated with immune-related adverse events (irAEs) among recipients, some of which are life-threatening. Oncolytic virotherapy is a potentially viable approach to improving the efficacy of ICI therapy because of their ability to selectively replicate and lyse tumor cells, release tumor-associated antigens (TAAs), induce inflammatory response and promote lymphocyte infiltration in tumors. Methods A recombinant oncolytic adenoviruses (OAd), denoted ZD55-aPD-L1 scFv, which carried the expression cassette for anti-PD-L1 scFv was constructed by molecular cloning. Western blot and ELISA assay were performed to detect aPD-L1 scFv expression. Flow cytometry were used to analyse PD-L1 expression and count tumor cells. Co-culture assay of human peripheral blood mononuclear cells (PBMCs) with tumor cells in vitro and triple-negative breast cancer (TNBC) MDA-MB-231 tumor-bearing model in vivo were evaluated the antitumor effects of recombinant oncolytic adenoviruses ZD55-aPD-L1 scFv. Results We found that cells infected with recombinant oncolytic adenovirus ZD55-aPD-L1 scFv can effectively express aPD-L1 scFv, which function similarly to its full-length anti-PD-L1 antibody. PBMCs have inherently very limited killing effect on tumor cells even with administration of anti-PD-L1 antibody as observed from our in vitro co-cultures. Treatment consisting of ZD55 alone or ZD55 combined with anti-PD-L1 antibody yielded mediocre antitumor efficacy in subsequent in vitro and in vivo investigations, but were all substantially surpassed by the synergistic antitumor effects observed with ZD55-aPD-L1 scFv treatment. We show that the concomitant direct oncolysis by the recombinant OAd and localized autocrine/paracrine interception of PD-1:PD-L1 checkpoint interaction mediated by ZD55-aPD-L1 scFv-infected cells is exceedingly superior to co-administration of ZD55 and anti-PD-L1 antibody in the human TNBC mice model. Conclusions Our results provided evidence for the development of novel strategies, in this case an anti-PD-L1 scFv-armed OAd, to bolster immune responses to ‘cold’ tumors and to improve therapeutic responsiveness to ICIs.
研究领域:
肿瘤学
·
免疫疗法
·
分子生物学
·
癌症研究
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产品关联
DOI
PubMed
高影响因子
Frontiers in Bioengineering and Biotechnology
·
2022
·
IF 6.064
Qian Xiaojun,Shi Ronghua,Chen Jian,Wang Yong,Han Xinghua,Sun Yubei,Ling Cong,Wang Gang,Xu An-Wu,Pan Yueyin
Chemotherapy, as one main strategy to relieve tumor progression, has a weak effect on triple-negative breast cancer (TNBC) chest wall metastasis. The development of near-infrared (NIR) light-responsive nanomaterials for chemodynamic therapy (CDT) and photothermal therapy (PTT) is a promising platform but still challenging in biomedicine. This study reports a peroxidase mimicking nanozyme (Fe-N-C SAzyme) against TNBC by CDT and PTT. Fe-N-C SAzyme generated reactive oxygen species (ROS) by decomposing H2O2 into hydroxyl radicals (•OH) and also induced light-to-heat conversion under the exposure of 808 nm laser irradiation. With these biological characteristics, the obtained Fe-N-C SAzymes displayed enhanced cell cytotoxicity and inhibition of cancer cell proliferation both in vitro and in vivo at a low dose of nanoagent and a moderate NIR laser power density. Besides, Fe-N-C nanoagent with its excellent ROS generation brought metabolic reprogramming of elevated glycolysis in tumor cells. In vivo experiments, when combined with PTT, the enhanced antitumor effect was found by the elimination of M-MDSC in tumor microenvironment. Fe-N-C SAzymes can serve as a new synergistic CDT and PTT nanoagent to simultaneously reprogram tumor metabolism and tumor microenvironment. It will provide prospects for chemodynamic/photothermal combined cancer therapy for TNBC chest wall metastasis based on the use of a single nanosystem.
研究领域:
癌症治疗
·
纳米技术
·
生物医学工程
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
·
IF 2.705
Conghui Fan,Fanhui Kong,Dattatrya Shetti,Bao Zhang,Yeguo Yang,Kun Wei
Currently, breast cancer has become the most commonly diagnosed malignancy among females and triple negative breast cancer (TNBC) is a highly aggressive and metastatic subtype. The natural polyphenolic compound, resveratrol (3, 4’, 5-trihydroxy-trans-stilbene, RES), has drawn great attention for its potential against TNBC. However, due to the poor aqueous solubility, the bioactivity of RES against TNBC is extremely hampered. In this study, oxidized mesoporous carbon nanoparticles (oMCNs) with size below 200 nm and excellent water dispersibility were synthesized using mild oxidation method and RES was successfully encapsulated into the pores of oMCNs with high drug loading efficiency (24.8% w/w). oMCNs exhibited good biocompatibility and excellent cellular uptake efficiency. Compared to pure RES, oMCNs-RES greatly improved the saturated solubility and in vitro release property. In vitro cytoxicity assay and apoptosis analysis showed that oMCNs-RES induced enhanced cytotoxic effect and pro-apoptosis effect mediated via the PARP and Caspase-3 protein cleavage in TNBC cell line, respectively. These results demonstrate oMCNs have the potential to deliver hydrophobic drugs and oMCNs-RES are promising in treating TNBC.
研究领域:
肿瘤学
·
纳米技术
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2021
·
IF 6.244
Li Ke,Li Ruyue,Zhou Baona,Chen Jing,Lan Kai,Zhan Wenhua,Chen Di,Zhang Tao,Li Xueping
Triple-negative breast cancer (TNBC) has inadequate treatment approaches and a poor prognosis. It is urgent to develop new treatment approaches for TNBC. The combination of photothermal therapy (PTT) and chemotherapy is a very effective potential therapy for TNBC. However, asynchronous accumulation, unclear efficacy, and toxic side effects hinder the further promotion of this method. Therefore, we designed and constructed a new type of nanocarriers, the cascade release near-infrared imaging (NIFI) & thermal-chemo combination nanoparticles (CNC NPs), that can release drugs through the cascade of ultrasound triggering and pH responding to achieve the synchronous tumor accumulation, monitoring and synergistic treatment of two functional molecules. The key material of CNC NPs is the polydopamine (PDA), which, through self-assembling, forms a rigid shell that contains doxorubicin (DOX) and NIF fluorescent dye IR780 on the surface of the perfluorohexane (PFH) microbubbles. The results show that CNC NPs have a hollow core-shell structure with an average particle size of 97.3 ± 27.2 nm and have exceptional colloidal stability and photothermal conversion efficiency. The NPs can effectively perform cascade drug release through ultrasound triggering and pH responding. CNC NPs have good in vivo biological safety and excellent fluorescence imaging, drug delivery, and therapeutic abilities in the TNBC models. These results provide an experimental basis for the development of new clinical treatment methods for TNBC.
研究领域:
肿瘤学
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纳米技术
·
诊疗学
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生物医学工程
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Nano Materials
·
2024
·
IF 5.3
Jie Li,Yufeng Gu,Wenwen Sun,Baoyu Wen,Bin Li,Jie Liu,Zhihong Sun,Qi Zhao,Chengming Sun
Triple-negative breast cancer (TNBC) poses a significant challenge owing to its complex pathological features and treatment resistance. In recent years, immune checkpoint blockade (ICB) therapy has shown satisfactory results in the treatment of TNBC. ICB therapy targeting T cells’ inhibitory receptors and innate immune checkpoints has gradually become a research hotspot. However, a study has found that compared with single immune checkpoint inhibition, dual ICB has a more significant therapeutic effect. This study aimed to develop an engineered nanocarrier, aLS@VpNPs, loaded with the photosensitizer verteporfin and coated with TNBC cell membranes loaded with antilymphocyte activation gene-3 (anti-LAG3) and sialic acid binding immunoglobulin-like lectin 10 (Siglec10) proteins for delivering combination therapies. The biomimetic vector can mimic the surface characteristics of tumor cells, showing better biocompatibility and efficient tumor-targeting ability. Under photodynamic therapy (PDT), reactive oxygen species (ROS) are generated at the tumor site to directly kill cancer cells and induce immunogenic cell death, transforming “cold tumors” into “hot tumors” and further enhancing the efficacy of dual ICB targeting T cells and macrophages. In summary, this approach improves drug delivery efficiency and therapeutic precision and activates the host immune system through the synergistic mechanisms of PDT and ICB. In addition, the study reveals potential mechanisms for the combined therapy in modulating the tumor microenvironment, offering effective strategies and directions for TNBC treatment.
研究领域:
肿瘤学
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免疫治疗
·
纳米技术
·
癌症研究
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治疗学
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）