MOLECULAR PHARMACEUTICS
·
2018
·
IF 4.556
Yijia Yin,Qian Hu,Chenfeng Xu,Qi Qiao,Xianya Qin,Qingle Song,Yang Peng,Yongdan Zhao,Zhiping Zhang
A dual-sensitive nanoparticle delivery system was constructed by incorporating an acid sensitive hydrazone linker into thermosensitive nanoparticles (TSNs) for co-encapsulating doxorubicin (DOX) and interferon γ (IFNγ) and to realize the co-delivery of chemotherapy and immunotherapy agents against melanoma. DOX, a chemotherapeutic drug, was conjugated to TSNs by a pH-sensitive chemical bond, and IFNγ, a potent immune-modulator, was absorbed into TSNs through the thermosensitivity and electrostatics of nanoparticles. Consequently, the dual sensitive drug-loaded TSN delivery systems were successfully built and showed an obvious core–shell structure, good encapsulation efficiency of drugs, sustained and sensitive drug release, prolonged circulation time, as well as excellent synergistic antitumor efficiency against B16F10 tumor bearing mice. Moreover, the combinational antitumor immune responses of hydrazone bearing DOX/IFNγ-TSN (hyd) were strengthened by activating Th1-type CD4+ T cells, cytotoxic T lymphocytes, and natural killer cells, downregulating the expression levels of immunosuppressive cytokines, such as IL10 and TGFβ, and upregulating the secretion of IL2 and TNFα. Taken together, the multifunctional TSNs system provides a promising strategy for multiple drugs co-delivery with distinct properties.
研究领域:
肿瘤学
·
药剂学
·
免疫学
✓ 已验证
DOI
PubMed
高影响因子
Small
·
2022
·Vol. 18
·期 29
·2107787
·
IF 15.153
Haifeng Liang,Lei Zhou,Zhichao Hu,Yuxiang Ge,Taiwei Zhang,Qing Chen,Ben Wang,Shunyi Lu,Wang Ding,Jian Dong,Fengfeng Xue,Libo Jiang
Low responsiveness to anti-programmed death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) for solid tumors indicates the presence of other immunosuppressive pathways. Siglec15, a newly discovered immune checkpoint, has been reported to repress immune responses in the tumor microenvironment (TME) and regulate osteoclast differentiation. However, the role of Siglec15 in the treatment for bone metastasis remains unclear. Herein, Siglec15 shows significantly higher expression in lung adenocarcinoma spinal metastasis (LUAD-SM) than in para-cancerous spinal tissues and primary LUAD. Subsequently, a TME-responsive hollow MnO 2 nanoplatform (H-M) loaded with Siglec15 siRNA and cisplatin (H-M@siS15/Cis) is developed, and the surface is modified with an aspartic acid octapeptide (Asp 8 ), thus allowing H-M to target spinal metastasis. High drug-loading capacity, good biocompatibility, effective tumor accumulation, and efficient Siglec15 silencing are demonstrated. Furthermore, the nanoparticles could reverse immunosuppression caused by tumor cells and tumor-associated macrophages (TAMs) and inhibit osteoclast differentiation via Siglec15 downregulation in vitro. In a LUAD-SM mouse model, H-M@siS15/Cis-Asp 8 exhibits superior therapeutic efficacy via synergetic immunochemotherapy and osteolysis inhibition. Taken together, this single nanoplatform reveals the therapeutic potential of the new immune checkpoint Siglec15 in LUAD-SM and provides a strategy to treat this disease.
研究领域:
肿瘤学
·
免疫学
·
纳米医学
·
骨生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Zhimeng Chen,Tiantian Wen,Xueyuan Wang,Lin Yang,Zhongjie Wang,Yanru Qin,Yixue Hu,Tianyu Zhang,Dongna Wang,Amin Liu,Liefeng Zhang,Meng Lei,Yongqiang Zhu
Herein, a cyclodextrin derivative (R6RGD-CMβCD) with tumor target and a carboxymethyl chitosan derivative (M2pep-CMCS) with tumor-associated macrophages 2 (TAM2) target were successfully synthesized, respectively. DOX-loaded nanoparticles (R6RGD-CMβ [email protected] NPs, RCNP DOX ) and R848-loaded nanoparticles ( [email protected] NPs, MCNP R848 ) were prepared. Furthermore, the RCNP DOX and MCNP R848 exhibited good DOX and R848 absorption. Meanwhile, the synergetic cell toxicity of RCNP DOX and MCNP R848 was found. Additionally, RCNP DOX + MCNP R848 nanoparticles greatly promoted the expression levels of cleaved Caspase3, which indicated that the nanoparticles could induce cell apoptosis. At the same time, the immunohistochemical images exhibited that RCNP DOX + MCNP R848 group could effectively transform the phenotype of tumor-associated macrophages. Importantly, in vivo experiments revealed that RCNP DOX + MCNP R848 NPs exerted excellent anticancer effects in tumor-bearing mice. To summarize, RCNP DOX + MCNP R848 NPs are effective anticancer treatment combining chemotherapy and immunotherapy, M2pep-CMCS and R6RGD-CMβCD are good delivery materials.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Lizhen Liang,Zixuan Ye,Jiayi Wu,Huazhen Lu,Wenzheng Liu,Lingtong Meng,Yanan Li,He Huang
Sialic acid, as the new immunosuppressive molecule, is positively correlated with tumor progression, metastasis, and drug resistance. Although targeting desialylation strategy has promising implications for regulating immunosuppressive environment and sensitizing chemotherapy, delivery strategies that integrate the amplifying effects of desialylation and immunogenic chemotherapy are still unexplored. Here, we engineered an Escherichia coli Nissle 1917 hybrid (SSE@ZIF-90/Oxa) to integrate the co-delivery of sialidase and immunogenic cell death inducers which were expected to boost strong antitumor response. In the tumor-hypoxic environment, engineered SSE bacteria exert hypoxia-responsive sialidase expression and periodic lysis to release sialidase, disrupting the sialoglycan-mediated immune suppression. ZIF-90/Oxa was hybridized on the surface of SSE to further induce ICD effect to recruit more infiltration of immune cells. In melanoma models in male mice, this SSE@ZIF-90/Oxa facilitated the co-delivery of sialidase and Oxa both deeply penetrated into and across tumor, suppressed the tumor, and prolonged the survival time of mice, by markedly increasing mature DCs, TNF-α + CD8 + T cells, and M1 macrophages, while reducing PD-1 + CD8 + T cells and Tregs, indicating effective activation of anti-tumor immune cells. Thus, our study provides an intelligent biohybrid therapeutic platform for boosting the combined effect of desialylation-based immunotherapy and immunogenic chemotherapy.
研究领域:
癌症治疗
·
免疫学
·
生物技术
·
药学
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Materials & Interfaces
·
2023
·
IF 9.5
Ziyi Xu,Yu Huang,Yihan Wu,Jiamei Chen,Sai-Wang Seto,George Pak-Heng Leung,Yin Cai,Jingjing Li,Jinming Zhang
Despite the acknowledged advantages of combined immunochemotherapy for tumor treatment, the high efficiency of co-delivery of these combined agents into the targeted tumor tissue is still challenging. Herein, based on a “three-birds-with-one-stone” strategy, a facile glycyrrhizic acid (GL)-lipid hybrid nanoplatform loading triptolide (TP/GLLNP) is designed to better address the dilemma. Differing from the traditional liposomes with dual-drug co-delivery NPs, GL with a cholesterol-like structure is primarily employed to construct the lipid membrane skeleton of the GL-based lipid nanoparticle (GLLNP), and then triptolide (TP) is readily loaded in the lipid bilayer of GLLNP. The fabricated GLLNP possessed similar drug loading efficacy, particle size, and storage stability; none of the hemolysis; even higher membrane fluidity; and lower absorbed opsonin proteins compared with the conventional liposomes. Compared to TP-loaded traditional liposomes (TP/Lipo), TP/GLLNP exhibits significantly enhanced cellular uptake, cytotoxicity, and apoptosis of HepG2 cells. In addition, GLLNP could ameliorate tumor immunosuppression by promoting tumor-associated macrophage polarization from M2 to M1 phenotype. Furthermore, enhanced retention and accumulation in the tumor area of GLLNP could be found. As expected, TP/GLLNP displayed synergistic anti-hepatocellular carcinoma efficacy in vivo. In conclusion, this study provides an inspirational strategy to combine the anti-HCC benefits of GL and TP using a novel dual-drug co-delivery nanosystem.
研究领域:
药学
·
纳米技术
·
肿瘤学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2022
·
IF 8.025
Mengting Lin,Yuqing Li,Haiyue Long,Yueling Lin,Zhuo Zhang,Fengyun Zhan,Manmei Li,Chaoxi Wu,Zhong Liu
Biomimetics plays an important role in cancer treatment since it can prolong the circulation of nanoparticles, enhance their delivery and retention in target tissues, and reduce the systemic toxicity of drugs and their carriers. In this study, we developed a biomimetic nanosystem consisting of chemotherapeutic and immunotherapeutic agents wrapped in cell membranes. Specifically, the anti-tumor drug doxorubicin (DOX) was loaded into a bacterial-derived immunomodulatory agent (low molecular weight curdlan, lCUR), and the lCUR-DOX was further wrapped in the red blood cell membrane for camouflage and prolonged circulation. The successful preparation of the [email protected] nanosystem was supported by various optical and morphological characterizations. In vitro studies indicated that the nanosystem can escape uptake by macrophages, inhibit the invasion of tumor cells, and reprogram M2 macrophages with an immunosuppressive phenotype into M1 macrophages with an immunopromoting phenotype via the MAPK signaling pathway while promoting the phagocytosis of macrophages. In vivo studies showed that the nanosystem effectively inhibits tumor growth in the A-375 tumor-bearing mouse model. Taken together, the above results support further development of the [email protected] platform for cancer immunochemotherapy in clinical applications.
研究领域:
癌症治疗
·
纳米技术
·
免疫学
·
药理学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2024
·
IF 14.3
Haisi Wu,Xianbao Sun,Kaiming Li,Jinyu Li,Hui Jiang,Dan Yan,Ya Lin,Yan Ding,Yawen Lu,Xiaole Zhu,Xufeng Chen,Xiaolin Li,Gaolin Liang,Huae Xu
Paclitaxel (PTX) is a first-line chemotherapeutic drug for non-small cell lung cancer (NSCLC) but it can induce indoleamine 2,3-dioxygenase (IDO) activation, which severely lowers down its immuno-chemotherapeutic effect. To address this issue, a smart peptide hydrogelator Nap–Phe–Phe–Phe–Lys–Ser–Thr–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap-T ), which co-assembles with PTX and an IDO inhibitor GDC0919 to form a hydrogel GP@Gel Nap-T, is rationally designed. Upon specific phosphorylation by pyruvate kinase M2 (PKM2), an overexpressed biomarker of NSCLC, Nap-T is gradually converted to Nap–Phe–Phe–Phe–Lys–Ser–Thr(H 2 PO 3 )–Gly–Gly–Lys–Ala–Pro–Arg–OH ( Nap-Tp ), leading to dehydrogelation and sustained release of PTX and GDC0919 within NSCLC tissues. The released PTX exerts chemotherapy on NSCLC cells as well as immunogenic cell death induction, while GDC0919 promotes the immuno-chemotherapeutic effect of PTX through IDO inhibition. We find that GP@Gel Nap-T enhances the infiltration of tumor-infiltrating immune cells and reduces the number of immunosuppressive cells in either tumor tissues or tumor-draining lymph nodes, thus enhancing the immuno-chemotherapy of PTX toward NSCLC. With this PKM2-responsive drug release strategy, the smart peptide hydrogel platform might be applied for NSCLC treatment in clinic in near future.
研究领域:
肿瘤学
·
药理学
·
免疫学
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2020
·
IF 10.317
Qilin Li,Jia Liu,Huiling Fan,Lin Shi,Yan Deng,Lei Zhao,Mengxi Xiang,Yunruo Xu,Xulin Jiang,Guobin Wang,Lin Wang,Zheng Wang
Immunogenic chemotherapy (IC) is a type of chemotherapy where certain chemodrugs induce immunogenic cancer cell death (ICD), which in turn arouses T cell antitumor immunity. However, IC concurrently upregulates a key immune suppressor, indoleamine-2,3-dioxygenase (IDO), in both cancer cells and immune cells . IDO-mediated immunosuppression significantly offsets IC's therapeutic benefits in cancer patients , suggesting a necessity of combination with IDO inhibitors. Here, we report an enzyme-, pH-, and redox-triple-sensitive nanosystem using mesoporous silica nanoparticles (MSNs) as a core encapsulating doxorubicin (DOX, an immunogenic chemodrug); the core is coated with a shell ( β -CD-PEI/Ge1MT) for co-delivering 1-methyl-D-tryptophan (1 MT, an IDO inhibitor). By using these responsivenesses sequentially triggering the release of 1 MT into tumor extracellular compartment and DOX into intracellular endo/lysosomal compartment, this nanosystem ( [email protected] ) precisely delivers the drugs to their target cells residing in different compartments. Released 1 MT uptake by IDO-expressing dendritic cells (DCs) and cancer cells suppresses IDO activity, reducing immunosuppressive Tregs' presence; DOX unloaded within cancer cells induces ICD, promoting effector T-cell infiltration . In two preclinical cancer models, [email protected] potentiate both tumor local and systemic antitumor immunity, suppressing primary tumor growth by 78% with an 83% reduction in metastatic foci, as well as extending animal survival, thus strongly demonstrating [email protected] GMTMSNs' clinical translational potential.
研究领域:
癌症研究
·
纳米技术
·
免疫疗法
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Shizhen Geng,Pengke Guo,Xinling Li,Yaru Shi,Jing Wang,Mengnian Cao,Yunya Zhang,Kaixiang Zhang,Airong Li,Haiwei Song,Zhenzhong Zhang,Jinjin Shi,Junjie Liu,Yiling Yang
Immune checkpoint blockade (ICB) therapy has been approved for breast cancer (BC), but clinical response rates are limited. Recent studies have shown that commensal microbes colonize a variety of tumors and are closely related to the host immune system response. Here, we demonstrated that Fusobacterium nucleatum (F.n), which is prevalent in BC, creates an immunosuppressive tumor microenvironment (ITME) characterized by a high-influx of myeloid cells that hinders ICB therapy. Administering the antibiotic metronidazole in BC can deplete F.n and remodel the ITME. To prevent an imbalance in the systemic microbiota caused by antibiotic administration, we designed a biomimetic nanovehicle for on-site antibiotic delivery inspired by F.n homing to BC. Additionally, ferritin-nanocaged doxorubicin was coloaded into this nanovehicle, as immunogenic chemotherapy has shown potential for synergy with ICB. It has been demonstrated that this biomimetic nanovehicle can be precisely homed to BC and efficiently eliminate intratumoral F.n without disrupting the diversity and abundance of systemic microbiota. This ultimately remodels the ITME, improving the therapeutic efficacy of the PD-L1 blocker with a tumor inhibition rate of over 90% and significantly extending the median survival of 4T1 tumor-bearing mice.
研究领域:
肿瘤学
·
免疫学
·
纳米技术
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Kangkang Liu,Lining Wang,Jing Peng,Yuanji Lyu,Yiming Li,Dengyi Duan,Wenyi Zhang,Guojiang Wei,Taipeng Li,Yuanjie Niu,Yang Zhao
Intravesical Bacillus Calmette–Guérin (BCG) is a well-established strategy for managing high-risk nonmuscle-invasive bladder cancer (NMIBC); however, over half of patients still experience disease recurrence or progression. Although the combined intravesical instillation of various chemotherapeutic drugs is implemented in clinical trials to enhance the BCG therapy, the outcome is far from satisfying due to severe irritative effects and treatment intolerance at high doses. Therefore, it is adopted the “biotin–streptavidin strategy” to doxorubicin (DOX)-encapsulated nanoparticles within live BCG bacteria (DOX@BCG) to improve treatment outcomes. Adherence of BCG to the bladder epithelium helps precisely target DOX@BCG to the local tumor cells and simultaneously increases intratumoral transport of therapeutic drugs. DOX@BCG effectively inhibits cancer progression and prolongs the survival of rats/mice with orthotopic bladder cancer owing to synergism between BCG-immunotherapy, DOX-chemotherapy, and DOX-induced immunogenic tumor cell death; furthermore, it exhibits improved tolerance and biosafety, and establishes antitumor immunity in the tumor microenvironment. Therefore, the drug-loaded live BCG bacterial delivery system holds considerable potential for clinical translation in the intravesical treatment of bladder cancer.
研究领域:
肿瘤学
·
药理学
·
免疫治疗
·
纳米技术
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2021
·Vol. 9
·期 9
·3453-3464
·
IF 6.843
Xiaofang Li,Wen Zhang,Jing Lin,Hao Wu,Yucen Yao,Jiayi Zhang,Chunrong Yang
The application of combination immune-chemotherapy makes up for the limitation of monotherapy and achieves superior antitumor activity against cancer. However, combinational therapy is always restricted by poor tumor targeted drug delivery efficacy. Herein, novel T cell membrane cloaking tumor microenvironment-responsive nanoparticles (PBA modified T cell membrane cloaking hyaluronic acid (HA)-disulfide bond-vitamin E succinate/curcumin, shortened as RCM@T) were developed. T cell membrane cloaking not only serves as a protection shell for sufficient drug delivery but also acts as a programmed cell death-1(PD-1) “antibody” to selectively bind the PD-L1 of tumor cells. When RCM@T is intravenously administrated into the blood stream, it accumulates at tumor sites and responds to an acidic pH to achieve a “membrane escape effect” and expose the HA residues of RCM for tumor targeted drug delivery. RCM accumulates in the cytoplasm via CD44 receptor mediated endocytosis and intracellularly releases antitumor drug in the intracellular redox microenvironment for tumor chemotherapy. T cell membrane debris targets the PD-L1of tumor cells for tumor immunotherapy, which not only directly kills tumor cells, but also improves the CD8+ T cell level and facilitates effector cytokine release. Taken together, the as-constructed RCM@T creates a new way for the rational design of a drug delivery system via the combination of stimuli-responsive drug release, chemotherapeutical agent delivery and cell membrane based immune checkpoint blockade immunotherapy.
研究领域:
肿瘤学
·
药理学
·
免疫疗法
·
纳米技术
·
药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Yiyin Ruan,Huijie Han,Xin Guan,Weiwei Feng,Xiaojuan Cui
Among the three primary gynecological malignancies, ovarian cancer has the highest mortality rate, and its onset is often insidious. Despite standard treatments, relapse and drug resistance remain major challenges. Doxorubicin (DOX) is known to induce immunogenic cell death (ICD); however, some patients still experience tumor resistance and recurrence owing to tumor-driven immunosuppression. Indoleamine 2,3-dioxygenase (IDO), which is highly expressed in tumor tissues, impairs T-cell function and differentiation, thereby promoting immunosuppression. Consequently, combining the IDO inhibitor indoximod (IND) with DOX may reverse immunosuppression and enhance both T-cell–mediated and ICD-driven anticancer effects. However, both drugs are limited by high systemic toxicity and poor tumor targeting, necessitating the use of nanocarriers to improve delivery efficiency and minimize toxicity. This study aims to develop novel cell membrane–camouflaged liposomes capable of co-delivering IND and DOX (DOX/IND@cmLPs) for ovarian cancer therapy and to evaluate its anticancer effects in vitro and in vivo. The particle size of DOX/IND@cmLPs is measured as 111.7 ± 2.7 nm using a Malvern Zetasizer Pro, with a zeta potential of −22.4 ± 4.00 mV. Entrapment efficiency (EE) is assessed using ultra-high performance liquid chromatography and ultraviolet spectrophotometry, yielding EE values of 85.1% ± 3.4% for DOX and 23.9% ± 1.3% for IND. At both pH 7.4 and pH 5.5, DOX release from DOX/IND@cmLPs is rapid during the first 24 hours, followed by a slower, more sustained release. Coomassie Brilliant Blue staining and Western Blot analysis confirmed successful encapsulation of the cell membrane in the liposomes. The potent antitumor effect of DOX/IND@cmLPs is demonstrated via CellTiter-Glo assays in vitro. Flow cytometry and immunofluorescence staining revealed an increased ratio of CD8 + T cells to Treg cells in tumor tissues, suggesting that DOX/IND@cmLPs may partially reverse local tumor-induced immunosuppression. Reduced Ki-67 expression and increased TdT-mediated dUTP nick-end labeling positive cell ratios in tumor sections indicated that DOX/IND@cmLPs treatment suppressed tumor proliferation and promoted apoptosis. Immunohistochemistry showed alterations in mammalian target of rapamycin (mTOR)-related pathway proteins in tumors. Furthermore, DOX/IND@cmLPs could induce an abscopal effect and provide long-lasting tumor suppression in a subcutaneous mouse model. In this study, a formulation of DOX/IND-loaded liposomes camouflaged with ovarian cancer cell membranes is successfully developed, and their stable physicochemical properties are confirmed. As an effective nanodrug delivery system, DOX/IND@cmLPs exhibited enhanced tumor-targeting and immune-mediated anticancer activity both in vitro and in vivo, indicating their potential as a platform for future combined chemotherapy and immunotherapy.
研究领域:
纳米医学
·
癌症免疫治疗
·
药物递送系统
·
制药纳米技术
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）