ACS Nano
·
2024
·
IF 15.8
Shu Liang,Lingyun Xiao,Tian Chen,Paola Roa,Emiliano Cocco,Zhangwen Peng,Liu Yu,Meiying Wu,Jie Liu,Xizhe Zhao,Wenbin Deng,Xiongjun Wang,Chao Zhao,Yang Deng,Yang Mai
Intraperitoneal co-delivery of chemotherapeutic drugs (CDs) and immune checkpoint inhibitors (ICIs) brings hope to improve treatment outcomes in patients with peritoneal metastasis from ovarian cancer (OC). However, current intraperitoneal drug delivery systems face issues such as rapid drug clearance from lymphatic drainage, heterogeneous drug distribution, and uncontrolled release of therapeutic agents into the peritoneal cavity. Herein, we developed an injectable nanohydrogel by combining carboxymethyl chitosan (CMCS) with bioadhesive nanoparticles (BNPs) based on polylactic acid-hyperbranched polyglycerol. This system enables the codelivery of CD and ICI into the intraperitoneal space to extend drug retention. The nanohydrogel is formed by cross-linking of aldehyde groups on BNPs with amine groups on CMCS via reversible Schiff base bonds, with CD and ICI loaded separately into BNPs and CMCS network. BNP/CMCS nanohydrogel maintained the activity of the biomolecules and released drugs in a sustained manner over a 7 day period. The adhesive property, through the formation of Schiff bases with peritoneal tissues, confers BNPs with an extended residence time in the peritoneal cavity after being released from the nanohydrogel. In a mouse model, BNP/CMCS nanohydrogel loaded with paclitaxel (PTX) and anti-PD-1 antibodies (αPD-1) significantly suppressed peritoneal metastasis of OC compared to all other tested groups. In addition, no systemic toxicity of nanohydrogel-loaded PTX and αPD-1 was observed during the treatment, which supports potential translational applications of this delivery system.
研究领域:
药学
·
生物医学工程
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肿瘤学
·
药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2024
·
IF 6.1
Xuedan Han,Jialei Liu,Yidong Zhang,Eric Tse,Qiyi Yu,Yu Lu,Yi Ma,Lufeng Zheng
Anlotinib has strong antiangiogenic effects and leads to vessel normalization. However, the "window period" characteristic in regulating vessel normalization by anlotinib cannot fully explain the long-term survival benefits achieved through combining it with other drugs. In this study, through RNA sequencing and label-free quantitative proteomics analysis, we discovered that anlotinib regulated the expression of components of the extracellular matrix (ECM), leading to a significant reduction in ECM stiffness. Our bioinformatic analysis revealed a potential positive relationship between the ECM pathway and gefitinib resistance, poor treatment outcomes for programmed death 1 (PD-1) targeting, and unfavourable prognosis following chemotherapy in lung cancer patients. We administered anlotinib in combination with these antitumour drugs and visualized their distribution using fluorescent labelling in various tumour types. Notably, our results demonstrated that anlotinib prolonged the retention time and distribution of antitumour drugs at the tumour site. Moreover, the combination therapy induced notable loosening of the tumour tissue structure. This reduction was associated with decreased interstitial fluid pressure and tumour solid pressure. Additionally, we observed that anlotinib effectively suppressed the RhoA/ROCK signalling pathway. These findings suggest that, in addition to its antiangiogenic and vessel normalization effects, anlotinib can increase the distribution and retention of antitumour drugs in tumours by modulating ECM expression and physical properties through the RhoA/ROCK signalling pathway. These valuable insights contribute to the development of combination therapies aimed at improving tumour targeting in cancer treatment.
研究领域:
肿瘤学
·
药理学
·
癌症生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Meng He,Wei Xu,Yuxin Dan,Yue Pan,Yingying Li,Mingsheng Chen,Chang-Ming Dong
It is challenging for nanovaccines (NVs) to effectively deliver antigens/neoantigens to prime specifically potent immunities and remodel immunosuppressive tumor microenvironment (TME) for combating immune “cold” cancers. Herein, a novel kind of mannosylated fluoropolypeptide NVs of MFPCOFG (i.e., mannosylated fluoropoly( D,L -cysteine) ovalbumin-loaded Fe 2+ -gallic acid) is designed that synergistically integrates triple antigen-metal-thermoimmunity to remodel immunosuppressive TME and achieve highly potent immunities. MFPCOFG plus near-infrared irradiation (NIR) effectively facilitated antigen uptake and escape, induced the maturation and antigen cross-presentations of dendritic cells and macrophages, polarized anti-inflammatory macrophage phenotype M2 into tumoricial M1, primed potent CD4 + /CD8 + T cells responses, proinflammatory cytokines secretion and immune memory effects, showcasing triple antigen-metal-thermoimmunity outperforming combo/mono-immunity. Importantly, both MFPCOFG + NIR and personalized NVs can remarkably enhance the tumor infiltration of CD4 + /CD8 + T and NK cells to boost potent immunities and long-lasting memory effects, reduce regulatory T (Tregs) and M2 to remodel immunosuppressive TME in B16-OVA and 4T1 models, achieving superior tumor prevention, ablation, and tumor relapse and metastasis inhibition, as further orchestrated with anti-PD-1. Consequently, this work opens up a new avenue to design biocompatible polypeptide nanovaccines with potent immune-priming and TME-remodeling capabilities, holding great potentials to combat immune “cold” cancers with clinic-used anti-PD-1 for cancer immunotherapy and personalized immunotherapy.
研究领域:
癌症免疫治疗
·
纳米技术
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免疫学
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生物医学工程
✓ 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
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药理学
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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 FUNCTIONAL MATERIALS
·
2019
·Vol. 29
·期 19
·1900004
·
IF 15.621
Jinrong Peng,Qian Yang,Yao Xiao,Kun Shi,Qingya Liu,Ying Hao,Fan Yang,Ruxia Han,Zhiyong Qian
Nanomedicine constructed by therapeutics has unique and irreplaceable advantages in biomedical applications, especially in drug delivery for cancer therapy. The strategy, however, used to construct the therapeutics-based nanomedicines with tumor microenvironmental factor responsiveness is still sophisticated. In this study, an easy-operating procedure is used to construct a therapeutics-based nanosystem with active tumor-targeting, enhanced penetration, and stimuli-responsive drug release behavior as well as programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) blockading mediated immunomodulation to enhance tumor immunotherapy. The matrix metalloproteinase-2 responsive peptide with the existence of Lyp-1 sequence contributes to the success of active tumor-targeting and the enhancement of the penetration of the nanoparticles in tumor tissue. The obtained nanosystem strikingly inhibits the primary tumor growth in the first 24 h (more than 97.5% of tumor cells are inhibited), and total inhibition can be achieved with the combination of photothermal therapy. IR820, which is served as the carrier for the therapeutics, is used as a photosensitizer for photothermal therapy. The progress and aggression of distal tumor has further been alleviated by a d -peptide which is an antagonist for PD-1/PD-L1 blockage. Therefore, a therapeutics-constructed multifunctional nanosystem is provided to realize a combinational therapeutic strategy to enhance the therapeutic outcome.
研究领域:
癌症治疗
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纳米医学
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药学
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免疫治疗
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生物医学工程
✓ 已验证
产品关联
DOI
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
·
纳米技术
·
癌症研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ORAL PATHOLOGY & MEDICINE
·
2021
·Vol. 51
·期 1
·74-85
·
IF 4.253
Jing-Ya Yang,Fang Wang,Gang Zhou
Background Oral lichen planus (OLP) is a T-cell-mediated chronic inflammatory disease with uncertain aetiology. Mucosal-associated invariant T (MAIT) cells and γδT cells are unconventional, innate-like T cells with immunoregulatory capacity. This study aimed to investigate the potential effects of MAIT and γδT cells on the pathogenesis of OLP. Methods Circulating MAIT cells and γδT cells were identified using flow cytometry. Surface proteins including CD4, CD8, CD69, CD103, CD49d, programmed death-1 (PD-1) and its ligand PD-L1 were assessed. Cytokines containing interleukin (IL)-4, IL-17, interferon (IFN)-γ, granzyme B and tumour necrosis factor (TNF)-α released by MAIT and γδT cells were measured following PMA and ionomycin stimulation. Results Circulating MAIT and γδT cells were deficient in OLP. The percentage of CD4 + , CD69 + , CD103 + and PD-1 + MAIT cells was increased in OLP, while that of CD8 + and CD49d + MAIT cells was decreased. The percentage of CD103 + , PD-1 + and PD-L1 + γδT cells was upregulated in OLP. Both the MAIT and γδT cells in OLP produced less IL-4 than controls. The granzyme B-producing MAIT cells were increased, while γδT cells secreting granzyme B and TNF-α were reduced in OLP. IL-17 and IFN-γ in OLP MAIT and γδT cells were not significantly different from that in controls. The frequency of OLP MAIT cells and the MAIT/γδT rate were positively associated with the disease severity. Conclusion The deficient MAIT and γδT cells expressing functional proteins and releasing cytokines may play an immunoregulatory role in the pathogenesis of OLP.
研究领域:
免疫学
·
炎症
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口腔疾病
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细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
World Journal of Gastrointestinal Oncology
·
2025
·Vol. 17
·期 9
·110166
·
IF 2.5
Yan-Li Xing,Hong-Mei Li,Xiao-Ming Pang,Ying Zhang,Ting Yang,Yan-Hong Li,De-Chuan Liu,Yang-Yang Ma,Li-Zhi Niu
BACKGROUND Irreversible electroporation (IRE) represents an innovative localized technique for tumor ablation, possessing the capacity to activate the immune response of the host. However, this method alone is inadequate to halt cancer progression, necessitating the integration of additional strategies to achieve effective immunotherapy. AIM To investigate the effects and underlying mechanisms of antitumor immunity derived from the synergistic application of IRE and anti-programmed cell death protein 1 (PD-1) therapy within a murine model of hepatocellular carcinoma. METHODS C57BL-6 mice with tumor growth were divided into four separate cohorts: Control group; IRE group; Anti-PD-1 group; And IRE + anti-PD-1 group. The infiltration levels of T, B, and natural killer cells within the tumors, as well as the plasma concentrations of T helper type 1 cytokines (interleukin-2, interferon-γ, and tumor necrosis factor-β), were evaluated. Real-time polymerase chain reaction was utilized to quantify the expression of cluster of differentiation (CD) 8 (a marker indicative of CD8 + T cells) in the tumor specimens of the mice at various temporal intervals. Tumor growth trajectories were charted. RESULTS The results indicated that the IRE + anti-PD-1 group exhibited significantly heightened percentages of T lymphocyte infiltration, particularly CD4 + and CD8 + T cells, when compared to the control cohort. Additionally, this group displayed increased infiltration of natural killer and B cells, augmented cytokine levels, and elevated CD8 messenger RNA expression. A marked decrease in tumor volume was noted in the IRE + anti-PD-1 group, indicating enhanced therapeutic efficacy. CONCLUSION The combined application of IRE and checkpoint blockade elicits an antitumor immune response, leading to a more substantial reduction in tumor volume and improved therapeutic outcomes, thereby establishing a novel avenue for the ablation and immunotherapy of hepatocellular carcinoma.
研究领域:
肿瘤学
·
免疫治疗
·
癌症免疫学
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肝脏病学
·
转化医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Chengming Qu,Haitao Yuan,Ming Tian,Xiaodong Zhang,Peng Xia,Guangwei Shi,Rui Hou,Ji Li,Haibo Jiang,Zhiyong Yang,Tengxiang Chen,Zhijie Li,Jigang Wang,Yufeng Yuan
Pancreatic ductal adenocarcinoma (PDAC) is notorious for its resistance against chemotherapy and immunotherapy due to its dense desmoplastic and immunosuppressive tumor microenvironment (TME). Traditional photodynamic therapy (PDT) was also less effective for PDAC owing to poor selectivity, insufficient penetration, and accumulation of photosensitizers in tumor sites. Here, we designed a light-responsive novel nanoplatform targeting the TME of PDAC through tumor-specific midkine nanobodies (Nbs), which could efficiently deliver semiconducting polymeric nanoparticles (NPs) to the TME of PDAC and locally produce abundant reactive oxygen species (ROS) for precise photoimmunotherapy. The synthesized nanocomposite can not only achieve multimodal imaging of PDAC tumors (fluorescence and photoacoustic imaging) but also lead to apoptosis and immunogenic cell death of tumor cells via ROS under light excitation, ultimately preventing tumor progression and remodeling the immunosuppressive TME with increased infiltration of T lymphocytes. Combined with a PD-1 checkpoint blockade, the targeted PDT platform showed the best antitumor performance and markedly extended mice survival. Conclusively, this work integrating Nbs with photodynamic NPs provides a novel strategy to target formidable PDAC to achieve tumor suppression and activate antitumor immunity, creating possibilities for boosting efficacy of immunotherapy for PDAC tumors through the combination with precise local PDT.
研究领域:
肿瘤学
·
生物医学工程
·
纳米技术
·
免疫学
·
癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-15
·
IF 12.6
Liu Yu,Zhang Jia,Lai Chunyu,Wang Wenjun,Huang Yangyue,Bao Xuanwen,Yan Haimeng,Sun Xuqi,Liu Qiqi,Chen Dong,Dai Xiaomeng,Qian Xinyu,Zhao Peng
Immunotherapy, exemplified by immune checkpoint blockade (ICB), has been extensively employed in antitumor treatments. Nevertheless, its efficacy in addressing low-immunogenic tumors has not yielded satisfactory results, primarily due to the depletion and inadequate infiltration of effector T cells within the tumor microenvironment (TME). Here, we construct an injectable water-in-oil emulsion hydrogel to load clinically used Celastrol (Gel@Cel), which addresses the limitations of Cel’s hydrophobicity. Cel can both inhibit tumor cell proliferation and promote tumor cell apoptosis, while simultaneously inducing immunogenic cell death, through activation of the AKT and MAPK pathways. In a model of clinically refractory hepatocellular carcinoma with malignant ascites, intraperitoneal administration of Gel@Cel significantly inhibits tumor progression and activates antitumor immune effects through lipase-controlled release of Cel, as compared to free Cel. Intriguingly, the Gel@Cel induces the activation of dendritic cells, resulting in the infiltration of cytotoxic T cells in the TME of ascites. Furthermore, the administration of Cel increases the expression of programmed cell death protein ligand-1 (PD-L1) in tumor cells. Moreover, combining the PD-1 antibody (αPD-1) with Gel@Cel further enhances the antitumor effect and amplifies the immune activation. In conclusion, Gel@Cel exhibits promising therapeutic potential in the treatment of low-immunogenic tumors, especially when combined with ICB therapy.
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
ACS Nano
·
2024
·
IF 15.8
Xin Wan,Ying Zhang,Yiqun Wan,Mengmeng Xiong,Anqi Xie,Yongye Liang,Hao Wan
The biomimetic nanoparticles (NPs) possessing abilities of tumor targeting and multimodal therapy show great potential for efficient combat of colon cancer. Herein, we developed a multifunctional biomimetic nanoplatform (Fe3O4@PDA@CaCO3–ICG@CM) based on CaCO3-modified magnetic polydopamine (PDA) loaded with indocyanine green (ICG), which was encapsulated by a mouse lymphoma cell (EL4) membrane (CM) expressing functional proteins (i.e., lymphocyte function-associated antigen 1, LFA-1; transforming growth factor-β receptor, TGF-βR; programmed cell death protein 1, PD-1; and factor related apoptosis ligand, FasL). Under magnetic attraction and LFA-1/PD-1-mediated endocytosis, Fe3O4@PDA@CaCO3–ICG@CM efficiently targeted CT26 colon tumor cells. The released calcium ion (Ca2+) from the NPs triggered by acidic tumor microenvironment, the enhanced photothermal effect contributed by the combination of PDA and ICG, and FasL’s direct killing effect together induced tumor cells apoptosis. Moreover, the apoptosis of CT26 cells induced immunogenic cell death (ICD) to promote the maturation of dendritic cells (DCs) to activate CD4+/CD8+ T cells, thereby fighting against tumor cells, which could further be boosted by programmed death-ligand 1 (PD-L1) blockage and transforming growth factor-β (TGF-β) scavenging by Fe3O4@PDA@CaCO3–ICG@CM. As a result, in vivo satisfactory therapeutic effect was observed for CT26 tumor bearing-mice treated with Fe3O4@PDA@CaCO3–ICG@CM under laser irradiation and magnetic attraction, which could eradicate primary tumors and restrain distant tumors through dual tumor targeting-assisted multimodal therapy and eliciting adaptive antitumor immune response, generating the immune memory for inhibiting tumor metastasis and recurrence. Taken together, the multifunctional biomimetic nanoplatform exhibits superior antitumor effects, providing an insightful strategy for the field of nanomaterial-based treatment of cancer.
研究领域:
纳米技术
·
癌症研究
·
生物医学工程
·
免疫治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Yuzhao Zheng,Fanxue Bu,Chenfeng Xu,Tongyu Wu,Jianping Zhou,Weiyang Shen,Tingjie Yin
Immunosuppressive microenvironment and poor immunogenicity are two stumbling blocks in anti-tumor immune activation. Tumor associated macrophages (TAMs) play crucial roles in immunosuppressive microenvironment, while immunogenic cell death (ICD) is a typical strategy to boost immunogenicity. Herein, we developed a coordinative modular assembly-based self-reinforced nanoparticle, (CaO 2 /TA)-(Fe 3+ /BSA) which integrated CaO 2 , Fe 3+ -tannic acid coordinated networks and albumin under the instruction of molecular dynamics simulation. (CaO 2 /TA)-(Fe 3+ /BSA) could significantly enhance Fenton reaction through Fe 3+ self-reduction and H 2 O 2 self-sufficiency, and simultaneously increased intracellular accumulation of Ca 2+ . The self-augmented Fenton reaction with sufficient reactive oxygen species effectively repolarized TAMs and elicited ICD with Ca 2+ overload. Besides, (CaO 2 /TA)-(Fe 3+ /BSA) was confirmed to self-reinforce deep tumor drug delivery by “treatment-delivery” positive feedback based on gp60-mediated transcytosis and M2-like macrophages repolarization-mediated perfusion promotion. Resultantly, (CaO 2 /TA)-(Fe 3+ /BSA) effectively alleviated immunosuppression, provoked local and systemic immune response and potentiated anti-PD-1 antibody therapy. Our strategy highlights a facile and controllable approach to construct penetrated effective antitumor nano-immunotherapeutic agent.
研究领域:
癌症免疫治疗
·
纳米技术
·
药学
·
生物医学工程
✓ 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）