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Immunostimulant nanomodulator boosts antitumor immune response in triple negative breast cancer by synergism of vessel normalization and photothermal therapy

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Nano Research 2023年第8期16卷 11149-11163页

作者： Hao Jiang Yilang He Jia Zhao Ruimin Chang Hailun He Tan Li Xingyu Zhang Bo Shu Wenxuan Zhang Huaiyu Wang Jing Liu Shubing Zhang Yuetao Zhao Department of Biomedical Informatics School of Life SciencesCentral South UniversityChangsha 410013China Department of Biochemistry and Molecular Biology Hunan Province Key Laboratory of Basic and Applied HematologySchool of Life SciencesCentral South UniversityChangsha 410013China Department of Cell Biology School of Life SciencesCentral South UniversityChangsha 410013China The Department of Dermatology Xiangya Clinical Research Center for Cancer ImmunotherapyHunan Key Laboratory of Skin Cancer and PsoriasisHunan Engineering Research Center of Skin Health and DiseaseXiangya HospitalCentral South UniversityNo.87 Xiangya RoadChangsha 410008China Department of General Surgery The Second Xiangya HospitalCentral South UniversityChangsha 410011China State Key Laboratory of Natural and Biomimetic Drugs Department of Chemical BiologySchool of Pharmaceutical SciencesPeking University Health Science CenterBeijing 100191China Institute of Biomedicine and Biotechnology Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Tumor vascular dysfunction and immune suppression predict poor outcomes of tumor *** of photothermal therapy(PTT)and vessel normalization with tumor immunotherapy is promising to augment antitumor ***,we develop a potential immunostimulatory nanomodulator for treatment of triple-negative breast cancer(TNBC)treatment via synergism of PTT,vessel normalization,and priming of tumoral suppressive immune microenvironment by blocking transforming growth factor-β(TGF-β)*** nanomodulator,namely Vac@Apt@BPs,is developed by conjugation of TGF-βinhibitor Vactosertib(Vac)and nucleolin-recognizing aptamer(Apt)on the surface of black phosphorus nanoparticles(BPs).Vac@Apt@BPs show good accumulation in TNBC via aptamer-induced active targeting of *** the blockade of TGF-βsignaling,Vac@Apt@BPs effectively inhibit the formation of tumor neovascular,and normalize the vessels to recover vascular integrity and alleviate the hypoxia *** with the tumor eradication and immunogenic cell death via PTT,robust immune response was boosted by promoted maturation of dendritic cells,suppression of regulatory T cells,and stimulation of effective T *** synergistic therapeutic strategy potentially suppresses the growth of TNBC in mice.

关键词： vessel normalization photothermal therapy black phosphorus triple negative breast cancer transforming growth factor-β

Macrophage-camouflaged epigenetic nanoinducers enhance chemoimmunotherapy in triple negative breast cancer

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Acta Pharmaceutica Sinica B 2023年第10期13卷 4305-4317页

作者： Tong Gao Xiao Sang Xinyan Huang Panpan Gu Jie Liu Yongjun Liu Na Zhang Department of Pharmaceutics Key Laboratory of Chemical Biology(Ministry of Education)NMPA Key Laboratory for Technology Research and Evaluation of Drug ProductsSchool of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer(TNBC),but the clinical outcomes remain *** epigenetic regulation is associated with acquired drug resistance and T cell exhaustion,which is a critical factor for the poor response to chemoimmunotherapy in ***,macrophage-camouflaged nanoinducers co-loaded with paclitaxel(PTX)and decitabine(DAC)(P/D-mMSNs)were prepared in combination with PD-1 blockade therapy,hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor *** of macrophage vesicle confers P/D-mMSNs with tumor-homing ***,DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to ***,PTX induces immunogenic death of tumor cells,promotes phagocytosis of dead cells by dendritic cells,and recruits cytotoxic T cells to infiltrate ***,DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy.P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.

关键词： triple negative breast cancer Chemoimmunotherapy Epigenetics Demethylation Decitabine Immunogenic cell death Anti-tumor immunity Combination therapy

Light-controllable charge-reversal nanoparticles with polyinosinic-polycytidylic acid for enhancing immunotherapy of triple negative breast cancer

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Acta Pharmaceutica Sinica B 2022年第1期12卷 353-363页

作者： Lei Fang Zitong Zhao Jue Wang Ping Xiao Xiangshi Sun Yaping Ding Pengcheng Zhang Dangge Wang Yaping Li Collage of Sciences Shanghai UniversityShanghai 200444China State Key Laboratory of Drug Research&Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Pharmacy Yantai UniversityYantai 264005China Yantai Key Laboratory of Nanomedicine&Advanced Preparations Yantai Institute of Materia MedicaYantai 264000China

Nucleic acid drugs are highly applicable for cancer immunotherapy with promising therapeutic effects, while targeting delivery of these drugs to disease lesions remains challenging. Cationic polymeric nanoparticles have paved the way for efficient delivery of nucleic acid drugs, and achieved stimuli-responsive disassembly in tumor microenvironment(TME). However, TME is highly heterogeneous between individuals, and most nanocarriers lack active-control over the release of loaded nucleic acid drugs, which will definitely reduce the therapeutic efficacy. Herein, we have developed a lightcontrollable charge-reversal nanoparticle(LCCN) with controlled release of polyinosinic-polycytidylic acid [Poly(I:C)] to treat triple negative breast cancer(TNBC) by enhanced photodynamic immunotherapy. The nanoparticles keep suitably positive charge for stable loading of Poly(I:C), while rapidly reverse to negative charge after near-infrared light irradiation to release Poly(I:C). LCCN-Poly(I:C) nanoparticles trigger effective phototoxicity and immunogenic cell death on 4 T1 tumor cells, elevate antitumor immune responses and inhibit the growth of primary and abscopal 4 T1 tumors in mice. The approach provides a promising strategy for controlled release of various nucleic acid-based immune modulators, which may enhance the efficacy of photodynamic immunotherapy against TNBC.

关键词： Nanoparticles cancer immunotherapy Photodynamic therapy Polyinosinic-polycytidylic acid triple negative breast cancer Charge-reversal Tumor microenvironment ROS-responsive

Coordinated regulation of BACH1 and mitochondrial metabolism through tumor-targeted self-assembled nanoparticles for effective triple negative breast cancer combination therapy

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Acta Pharmaceutica Sinica B 2022年第10期12卷 3934-3951页

作者： Xuan Yang Yalong Wang Junke Zhao Hehui Rong Yujun Chen Mengting Xiong Xiaoxing Ye Shihui Yu Haiyan Hu School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China The First Affiliated Hospital of Guangxi Medical University Nanning 530000China Guangdong Provincial Key Laboratory of Chiral Molecules and Drug Discovery Sun Yat-sen UniversityGuangzhou 510006China

The poor prognosis of triple negative breast cancer(TNBC)results from a lack of approved targeted therapies coupled with aggressive proliferation and metastasis,which is associated with high recurrence and short overall *** we developed a strategy by employing tumor-targeted selfassembled nanoparticles to coordinately regulate BACH1(BTB domain and CNC homology 1)and mitochondrial *** BACH1 inhibitor hemin and mitochondria function inhibitor berberine derivative(BD)were used to prepare nanoparticles(BH NPs)followed by the modification of chondroitin sulfate(CS)on the surface of BH NPs to achieve tumor targeting(CS/BH NPs).CS/BH NPs were found to be able to inhibit tumor migration and invasion by significantly decreasing the amounts of tumor cell metabolites,glycolysis and metastasis-associated proteins,which were related to the inhibition of BACH1 ***,decreased mitochondrial membrane potential,activated caspase 3/9 and increased ROS production demonstrated coordinated regulation of BACH1 and mitochondrial *** a xenograft mice model of breast cancer,CS/BH NPs significantly inhibited tumor growth and metastasis due to the synergetic effect of hemin and BD without showing obvious toxicities for major *** sum,the results of efficacy and safety experiments suggest potential clinical significance of the prepared self-assembled CS/BH nanoparticles for the treatment of TNBC.

关键词： Coordinated regulation BACH1 Mitochondrial metabolism Hemin Berberine derivative Self-assembled nanoparticle triple negative breast cancer

Tellurium-driven maple leaf-shaped manganese nanotherapeutics reshape tumor microenvironment via chemical transition in situ to achieve highly efficient radioimmunotherapy of triple negative breast cancer

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Bioactive Materials 2023年第9期27卷 560-573页

作者： Wei Huang Sujiang Shi Haoran Lv Zhenyu Ju Qinghua Liu Tianfeng Chen Jieyang Medical Research Center Jieyang People’s HospitalTianfu Road 107Rongcheng DistrictJieyangGuangdong522000China Department of Nephrology The First Affiliated HospitalNHC Key Laboratory of Clinical Nephrology(Sun Yat-Sen University)and Guangdong Provincial Key Laboratory of NephrologySun Yat-sen UniversityGuangzhouChina Key Laboratory of Regenerative Medicine of Ministry of Education Institute of Aging and Regenerative MedicineJinan UniversityGuangzhou510632China Department of Chemistry Jinan UniversityGuangzhou510632China

The therapeutic efficacy of radioimmunotherapy against triple negative breast cancer(TNBC)is largely limited by the complicated tumor microenvironment(TME)and its immunosuppressive *** developing a strategy to reshape TME is expected to achieve highly efficient ***,we designed and synthesized a tellurium(Te)-driven maple leaf manganese carbonate nanotherapeutics(MnCO3@Te)by gas diffusion method,but also provided a chemical catalytic strategy in situ to augment ROS level and activate immune cells for improving cancer *** expected,with the help of H2O2 in TEM,MnCO3@Te heterostructure with reversible Mn3+/Mn2+transition could catalyze the intracellular ROS overproduction to amplify *** addition,by virtue of the ability to scavenge H+in TME by carbonate group,MnCO3@Te directly promote the maturation of dendritic cells and macrophage M1 repolarization by stimulator of interferon genes(STING)pathway activation,resulting in remodeling *** a result,MnCO3@Te synergized with radiotherapy and immune checkpoint blockade therapy effectively inhibited the breast cancer growth and lung metastasis in ***,these findings indicate that MnCO3@Te as an agonist,successfully overcome radioresistance and awaken immune systems,showing promising potential for solid tumor radioimmunotherapy.

关键词： Radioimmunotherapy triple negative breast cancer Tellurium Manganese carbonate Tumor microenvironment

Bioactive nanotherapeutic trends to combat triple negative breast cancer

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Bioactive Materials 2021年第10期6卷 3269-3287页

作者： Pallabita Chowdhury Upasana Ghosh Kamalika Samanta Meena Jaggi Subhash C.Chauhan Murali M.Yallapu Department of Pharmaceutical Sciences University of Tennessee Health Science CenterMemphisTNUSA Department of Biomedical Engineering School of EngineeringRutgers UniversityThe State University of New JerseyPiscatawayNJ08854USA Department of Immunology and Microbiology School of MedicineUniversity of Texas Rio Grande ValleyMcAllenTXUSA South Texas Center of Excellence in cancer Research School of MedicineUniversity of Texas Rio Grande ValleyMcAllenTXUSA

The management of aggressive breast cancer,particularly,triple negative breast cancer(TNBC)remains a formidable challenge,despite treatment *** newer therapies such as atezolizumab,olaparib,and sacituzumab can tackle the breast cancer prognosis and/or progression,but achieved limited survival benefit(s).The current research efforts are aimed to develop and implement strategies for improved bioavailability,targetability,reduce systemic toxicity,and enhance therapeutic outcome of FDA-approved treatment *** review presents various nanoparticle technology mediated delivery of chemotherapeutic agent(s)for breast cancer *** article also documents novel strategies to employ cellular and cell membrane cloaked(biomimetic)nanoparticles for effective clinical *** technologies offer a safe and active targeting nanomedicine for effective management of breast cancer,especially TNBC.

关键词： breast cancer treatment triple negative breast cancer Chemotherapy Nanoparticles Membrane cloaked nanoparticles Nanomedicine Biomimetic nanoparticles

RNA-seq analysis identified hormone-related genes associated with prognosis of triple negative breast cancer

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The Journal of Biomedical Research 2020年第2期34卷 129-138页

作者： Fei Chen Yuancheng Li Na Qin Fengliang Wang Jiangbo Du Cheng Wang Fangzhi Du Tao Jiang Yue Jiang Juncheng Dai Zhibin Hu Cheng Lu Hongbing Shen Department of breast Surgery Women's Hospital of Nanjing Medical UniversityNanjing Maternity and Child Health Care HospitalNanjingJiangsu 210004China Department of Epidemiology Center for Global HealthSchool of Public HealthNanjing Medical UniversityNanjingJiangsu 211116China Jiangsu Key Lab of cancer Biomarkers Prevention and TreatmentCollaborative Innovation Center for Cancer MedicineNanjing Medical UniversityNanjingJiangsu 211116China Department of Bioinformatics School of Biomedical Engineering and InformaticsNanjing Medical UniversityNanjingJiangsu 211116China Department of Clinical Management National Center for STD ControlInstitute of DermatologyChinese Academy of Medical SciencesNanjingJiangsu 210042China

triple negative breast cancer(TNBC) is an aggressive subtype of breast cancer that currently lacks effective biomarkers and therapeutic targets required to investigate the diagnosis and treatment of TNBC. Here we performed a comprehensive differential analysis of 165 TNBC samples by integrating RNA-seq data of breast tumor tissues and adjacent normal tissues from both our cohort and The cancer Genome Atlas(TCGA). Pathway enrichment analysis was conducted to evaluate the biological function of TNBC-specific expressed genes. Further multivariate Cox proportional hazard regression was performed to evaluate the effect of these genes on TNBC prognosis. In this report, we identified a total of 148 TNBC-specific expressed genes that were primarily enriched in mammary gland morphogenesis and hormone levels related pathways, suggesting that mammary gland morphogenesis might play a unique role in TNBC patients differing from other breast cancer types. Further survival analysis revealed that nine genes(FSIP1, ADCY5, FSD1, HMSD, CMTM5, AFF3, CYP2 A7, ATP1 A2,and C11 orf86) were significantly associated with the prognosis of TNBC patients, while three of them(ADCY5,CYP2 A7, and ATP1 A2) were involved in the hormone-related pathways. These findings indicated the vital role of the hormone-related genes in TNBC tumorigenesis and may provide some independent prognostic markers as well as novel therapeutic targets for TNBC.

关键词： RNA-seq triple negative breast cancer prognosis differential expression

Immunotherapy as maintenance treatment in metastatic triple negative breast cancer

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Journal of cancer Metastasis and Treatment 2021年第1期7卷 315-322页

作者： Tira J.Tan Jack J.Chan Rebecca A.Dent Division of Medical Oncology National Cancer CentreSingapore 169610Singapore.

Metastatic triple negative breast cancer(mTNBC)is an aggressive disease associated with a poor prognosis as compared to other subtypes of breast *** advances have been made in recent years with new approvals for PARP inhibitors for those patients who harbor germline BRCA mutations and immune checkpoint inhibitors for patients with programmed death ligand-1(PD-L1)expressing *** therapies are associated with favorable toxicity profiles and improved health-related quality of life when compared with *** therapy,now recognized as the mainstay for patients with ovarian malignancies,takes advantage of the benefit of low-intensity therapies to suppress a disease over a prolonged period of time following maximal response to induction *** strategy has been little explored in the treatment of ***,we briefly discuss the evidence to date lending credence to this treatment paradigm and examine the potential role of immunotherapy as maintenance in the management of mTNBC.

关键词： triple negative breast cancer maintenance therapy immunotherapy PARP inhibitor

EGFR signaling promotes resistance to CHK1 inhibitor prexasertib in triple negative breast cancer

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cancer Drug Resistance 2020年第4期3卷 980-991页

作者： Kevin J.Lee Griffin Wright Hannah Bryant Leigh Ann Wiggins Michele Schuler Natalie R.Gassman Department of Physiology and Cell Biology University of South Alabama College of MedicineMobileAL 36688USA Mitchell cancer Institute University of South AlabamaMobileAL 36604USA Department of Comparative Medicine University of South Alabama College of MedicineMobileAL 36688USA Department of Microbiology and Immunology University of South Alabama College of MedicineMobileAL 36688USA

Aim:Innate resistance to the CHK1 inhibitor prexasertib has been described,but resistance mechanisms are not *** aimed to determine the role epidermal growth factor receptor(EGFR)plays in innate resistance to prexasertib in triple negative breast cancer(TNBC).Methods:Using a panel of pre-clinical TNBC cell lines,we measured the sensitivity to *** examined the effect activation of EGFR had on prexasertib *** measured the synergy of dual blockade of EGFR with erlotinib and CHK1 with prexasertib in TNBC cell lines and ***:EGFR overexpression and activation increased resistance to CHK1 inhibition by *** promoted the phosphorylation of BCL2-associated agonist of cell death(BAD),inactivating its pro-apoptotic *** of EGFR reversed BAD phosphorylation,increasing sensitivity to ***:The use of prexasertib as a monotherapy in TNBC has been limited due to modest clinical *** demonstrated that EGFR activation contributes to innate resistance to prexasertib in TNBC and potentially other *** expression status should be considered in clinical trials examining prexasertib’s use as a monotherapy or combination therapy.

关键词： triple negative breast cancer CHK1 replication apoptosis drug resistance epidermal growth factor receptor mitogenic signaling