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1.
    
The well‐designed activation of dendritic cells (DCs) by enhancing the delivery of antigens and immunostimulatory adjuvants into DCs is a key strategy for efficient cancer immunotherapy. Antigen‐antibody immune complexes (ICs) are known to directly bind to and cross‐link Fc‐gamma receptors (FcγRs) on DCs, which induce enhanced migration of DCs to draining lymph nodes through the up‐regulation of the chemokine receptor CCR7 and cross‐presentation inducing cytotoxic T lymphocyte (CTL) response against tumor antigen. In this study, ICs mimicking synthetic vaccine nanoparticles (NPs) are designed and synthesized by the coating of poly (lactic‐co‐glycolic acid) (PLGA) NPs containing adjuvant (CpG oligodeoxynuleotides (ODNs) as toll‐like receptor 9 ligands) with ovalbumin (OVA) proteins (as model antigens) and by the formation of OVA–OVA antibody ICs. Through the combination of FcγRs‐mediated efficient antigen uptake and CpG ODNs‐based immunostimulation, the secretion of TNF‐α (12.3‐fold), IL‐6 (7.29‐fold), and IL‐12 (11‐fold), homing ability to lymph nodes (7.5‐fold), and cross‐presentation (83.8‐fold IL‐2 secretion) are dramatically increased in DCs treated with PLGA(IC/CpG) NPs. Furthermore, mice vaccinated with DCs treated with PLGA(IC/CpG) NPs induced significant tumor (EG7‐OVA) growth inhibition as well as prolonged survival through CTL‐mediated enhanced cytotoxicity, antigen‐specific responses, and IFN‐γ secretion.  相似文献   

2.
    
Neoantigen vaccines and adoptive dendritic cell (DC) transfer are major clinical approaches to initiate personalized immunity in cancer patients. However, the immunization efficacy is largely limited by the in vivo trajectory including neoantigens’ access to resident DCs and DCs’ access to lymph nodes (LNs). Herein, an innovative strategy is proposed to improve personalized immunization through neoantigen-loaded nanovaccines synergized with adoptive DC transfer. It is found that it enables selective delivery of neoantigens to resident DCs and macrophages by coating cancer cell membranes onto neoantigen-loaded nanoparticles. In addition, the nanovaccines promote the secretion of chemokine C-C motif ligand 2 (CCL2), CCL3, and C-X-C motif ligand 10 from macrophages, thus potentiating the access of transferred DCs to LNs. This immunization strategy enables coordinated delivery of identified neoantigens and autologous tumor lysate-derived undefined antigens, leading to initiation of antitumor T cell immunity in a personalized manner. It significantly inhibits tumor growth in prophylactic and established mouse tumor models. The findings provide a new vision for potentiating adoptive cell transfer by nanovaccines, which may open the door to a transformative possibility for improving personalized immunization.  相似文献   

3.
    
The principle cause of cardiovascular disease (CVD) is atherosclerosis, a chronic inflammatory condition characterized by immunologically complex fatty lesions within the intima of arterial vessel walls. Dendritic cells (DCs) are key regulators of atherosclerotic inflammation, with mature DCs generating pro‐inflammatory signals within vascular lesions and tolerogenic DCs eliciting atheroprotective cytokine profiles and regulatory T‐cell (Treg) activation. Here, the surface chemistry and morphology of synthetic nanocarriers composed of poly(ethylene glycol)‐b‐poly(propylene sulfide) copolymers to enhance the targeted modulation of DCs by transporting the anti‐inflammatory agent 1,25‐dihydroxyvitamin D3‐(aVD) and ApoB‐100‐derived antigenic peptide P210 are engineered. Polymersomes decorated with an optimized surface display and density for a lipid construct of the P‐D2 peptide, which binds CD11c on the DC surface, significantly enhance the cytosolic delivery and resulting immunomodulatory capacity of aVD in vitro. Weekly low‐dose intravenous administration of DC‐targeted, aVD‐loaded polymersomes significantly inhibit atherosclerotic lesion development in high‐fat‐diet‐fed ApoE?/? mice. The results validate the key role of DC immunomodulation during aVD‐dependent inhibition of atherosclerosis and demonstrate the therapeutic enhancement and dosage lowering capability of cell‐targeted nanotherapy in the treatment of CVD.  相似文献   

4.
    
The cancer vaccine is one of the potent cancer immunotherapies based on provoking antigen-specific adaptive immune responses in patients. Activating host antigen-presenting cells by delivering antigens and adjuvants is one of the most important requirements to enhance cancer vaccine efficacy. This study proposes an effective cancer vaccine platform based on injectable mesocellular foam (MCF) silica microparticles with a dual role capable of in situ recruitment of host dendritic cells (DCs) and intracellular delivery of antigens to the recruited DCs. Subcutaneously administrated MCF microparticles loaded with chemoattractant to DCs (GM-CSF), antigenic protein (OVA), and TLR9 agonist (CpG-ODN) lead to robust DC maturation and high antigen-specific T cell responses. The cell recruitment, DC activation, and T cell responses of MCF-based cancer vaccine are significantly higher than injectable mesoporous silica scaffold, of which role is mostly limited to the cell recruiting scaffold. These features of MCF lead to effective inhibition of tumor growth in prophylactic vaccine setting and lung metastatic cancer model, representing MCF enabling cell-recruiting scaffold formation and intracellular delivery of antigen can be a promising material platform for an enhanced cancer vaccine.  相似文献   

5.
    
Despite the approval of oncolytic virus (OV) therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost‐intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus‐based therapies. Herein, reported is a nanoassembly comprised of multivalent host–guest interactions between polymerized paclitaxel (pPTX) and nitric oxide‐incorporated polymerized β‐cyclodextrin (pCD‐pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of OV. The resultant pPTX/pCD‐pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell (DC) activation, and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD‐pSNO results in activation and expansion of DCs systemically, but with a corresponding expansion of myeloid‐derived suppressor cells and suppression of CD8+ T cell expansion. When combined with antibody targeting cytotoxic T lymphocyte antigen‐4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD‐pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo‐ and immunotherapeutic synergies of PTX and nitric oxide and suggests the potential for virus‐free nanoformulations to mimic the therapeutic action and benefits of OVs.  相似文献   

6.
    
The development of nanomaterials that combine diagnostic and therapeutic functions within a single nanoplatform is extremely important for molecular medicine. Molecular imaging with simultaneous diagnosis and therapy will provide the multimodality needed for accurate diagnosis and targeted therapy. Here, gold‐coated iron oxide (Fe3O4@Au) nanoroses with five distinct functions are demonstrated, integrating aptamer‐based targeting, magnetic resonance imaging (MRI), optical imaging, photothermal therapy. and chemotherapy into one single probe. The inner Fe3O4 core functions as an MRI agent, while the photothermal effect is achieved through near‐infrared absorption by the gold shell, causing a rapid rise in temperature and also resulting in a facilitated release of the anticancer drug doxorubicin carried by the nanoroses. Where the doxorubicin is released, it is monitored by its fluorescence. Aptamers immobilized on the surfaces of the nanoroses enable efficient and selective drug delivery, imaging, and photothermal effect with high specificity. The five‐function‐embedded nanoroses show great advantages in multimodality.  相似文献   

7.
    
To advance the understanding and potential treatment strategies for triple-negative breast cancer (TNBC), particularly focusing on its high metastatic propensity and uncertain molecular targets, a biomimetic tumor cell membrane-encapsulated nanodelivery system is developed for enhanced immunotherapy. This system is assembled with the second near-infrared (NIR-II) photothermal agent, chemotherapeutic drug, and programmed death-ligand 1 (PD-L1) inhibitors camouflaged by TNBC cell membranes. An NIR-II Ag2S quantum dots (QDs) is introduced for not only realizing pronounced imaging-guided photothermal therapy (PTT), but also co-activating immunogenic cell death (ICD) with chemotherapy. Homologous targeting and camouflage properties endowed the nanodelivery system with excellent biocompatibility and efficient delivery ability to the tumor site, demonstrating excellent synergistic therapeutic efficacy. The release of damage-associated molecular patterns (DAMP) marked the induction of ICD, crucial for reshaping the immune microenvironment. Further integration of α-PD-L1 achieved a 56.5% immune checkpoint inhibition rate, synergistically amplifying immune response to ultimately activate key cytokines, thereby achieving pronounced anti-tumor immunotherapy effects. Notably, this approach realized a considerable reduction of metastatic nodules by 51.2% in the TNBC lung metastasis model. The proposed nanodelivery system extended tumor remission and effectively reduced lung metastasis, paving the way for a reliable and promising approach in TNBC immunotherapy.  相似文献   

8.
    
Photodynamic therapy (PDT) has received extensive attention as a promising cancer treatment approach. Still, challenges to in vivo photodynamic therapy have existed for decades. First, the “always on” nature of conventional photosensitizers will cause damage to normal tissues thereby limiting the treatment efficiency of PDT. Second, the hypoxic TME protects cancer stem cells (CSCs) deeply harbored in the center of tumors from PDT administration, thus contributing to the recrudescence and metastasis of tumors. Herein, a ROS-triggered self-immolative therapeutic prodrug ( Mu-PS ) is reported, comprising of an activatable photosensitizer, an indomethacin (IMC) part, and a ROS-responsive trigger, for the anti-stemness chemical and photodynamic therapy of tumors. Intriguingly, Mu-PS can target the tumor and selectively release the photosensitizer and IMC upon the activation of TME-related ROS, generating massive phototoxic 1O2 to kill most non-CSCs tumor cells under the action of PDT and block the growth of CSCs by IMC, hence, it multiplies the therapeutic index. Noteworthy, the anti-stemness mechanism of IMC in tumors is confirmed and elucidated for the first time. Overall, this study introduces a self-immolatative prodrug for combined CSCs-involved chemical therapy and activatable PDT for tumors and provides a design paradigm of prodrug for the precise prognosis and treatment of tumors.  相似文献   

9.
    
Metastatic triple-negative breast cancer (TNBC) has a poor prognosis and high mortality with no effective treatment options, and immunotherapy is highly anticipated as a potential treatment but is limited by the lack of tumor-infiltrating T lymphocytes in TNBC. Herein, red blood cell (RBC) membrane-camouflaged polyphosphoester (PPE) nanoparticles (RBC@PPEMTO/PFA) are prepared as the nanocarriers of mitoxantrone (MTO) and perfluoroalkane (PFA) for synergized immunotherapy. The encapsulated MTO can generate heat and reactive oxygen species (ROS) to achieve photothermal and photodynamic therapy; moreover, ROS further triggers the self-accelerating release of MTO from the ROS-sensitive PPE core to enable chemotherapy. The RBC@PPEMTO/PFA-mediated sequential photothermal/photodynamic/chemotherapy efficiently promotes the infiltration of CD8+ T cells into TNBC tumor tissue and synergizes the therapeutic activity of an immune checkpoint blockade antibody for metastatic TNBC treatment in distant and lung metastasis models. This biomimetic nanomedicine of MTO provides a convenient and available strategy to sensitize TNBC to immune checkpoint blockade antibody.  相似文献   

10.
    
Here, described are additional treatment strategies that make use of human mesenchymal stem cell (hMSC)‐based local immunotherapeutic agents for the treatment of solid tumors. Dibenzocyclooctyne‐poly(ethylene glycol)‐pheophorbide A conjugates are engineered for cell surface conjugation by copper‐free click chemistry and are subsequently conjugated to hMSC (hMSC‐DPP). hMSC‐DPP can recognize and migrate toward cancer lesions, where they secrete pro‐inflammatory cytokines such as interleukin (IL)‐6, IL‐8, and heat shock protein 70 in pursuance of photodynamic therapy‐mediated cell death. The secreted immune factors trigger interferon gamma, IL‐2, IL‐4, IL‐12, and granulocyte‐macrophage colony‐stimulating factor, resulting in the local accumulation of T cells, B cells, natural killer cells, and antigen presenting cells at the tumor site. Treatment with hMSC‐DPP induces the accumulation of cytokines at the cancer site and minimizes systemic immune‐based side effects. This strategy is expected to increase the vulnerability of cancer cells to immune cells and cytokines, thus aiding in the development of a robust treatment platform for cancer immunotherapy.  相似文献   

11.
12.
    
The combination of chemotherapy and immunotherapy holds great potential in clinical treatment of advanced cancers. Whereas, the therapeutic outcome of chemotherapeutic and immune regulator is suboptimal due to their poor tumor availability and severe off-target toxicity. Herein, self-carrier nanoparticles (PSMT NPs) integrating a paclitaxel (PTX) prodrug and indoleamine 2,3-dioxygenase 1 (IDO) inhibitor (1-methyl-tryptophan, 1MT) for tumor-specific chemo-immunotherapy is constructed. After internalization by cancer cells, PSMT NPs can respond to endogenous redox stimulus, and release PTX and 1MT. The released PTX can not only promote cell apoptosis via the intervention of cell mitosis but also initiate immunogenic cell death to facilitate the recruitment and activation of tumor-infiltrating cytotoxic T lymphocytes. The concomitant 1MT can inhibit the IDO activity to exhaust regulatory T cells, thereby synergistically activating cytotoxic T lymphocytes. PSMT NPs exhibit potentiated antitumor output toward triple-negative breast cancer and negligible systemic toxicity. This facile and versatile nanoplatform provides a promising strategy to cooperatively activate antitumor immunity for potentiated chemo-immunotherapy.  相似文献   

13.
    
Tumor immunotherapy has emerged as one of the most promising clinical techniques to treat cancer tumors. Despite its clinical application, the cancerous immunosuppressive microenvironment limits the therapeutic efficiency of the treatment. To generate a stronger immunogenic therapeutic effect, herein, a platinum complex for chemotherapy and a BODIPY photosensitizer for photodynamic therapy are encapsulated into multimodal type II immunogenic cell death (ICD) induce nanoparticles. As the platinum complex and the photosensitizer are able to induce type II ICD, an exceptionally strong immune response is observed in triple-negative breast cancer cells. While remaining stable and therefore poorly cytotoxic in the dark, the nanomaterial is found to quickly dissociate upon exposure to near-infrared light, causing a multimodal mechanism of action in cancer cells as well as multicellular tumor spheroids through combined chemotherapy, photodynamic therapy, and immunotherapy. The nanoparticles are found to nearly fully eradicate a triple-negative breast cancer tumor and therefore to strongly enhance the survival of tumor-bearing mice models using low drug and light doses.  相似文献   

14.
目的:探讨LAMS对胃癌细胞化疗的增敏作用。方法:RT-PCR及免疫组化法测定LAMS作用胃癌细胞前后Bcl-2基因蛋白含量;MTT法分别测定5-Fu、MTX、MMC、EPI、CTX与LAMS联合及单独作用胃癌细胞的ID50以及有效作用时间。结果:LAMS使胃癌细胞Bcl-2 mR-NA及基因蛋白表达下降,使胃癌细胞对5-Fu、MTX、MMC、EPI、CTX的敏感度增加、有效作用时间延长。结论:LAMS可有效地增加胃癌细胞对5-Fu、MTX、MMC、EPI、CTX的敏感性。  相似文献   

15.
    
Unsatisfied cytoreductive surgery predicts worse clinical outcomes. Previous studies have found that cyclophosphamide (CTX) is a rhythmic immune modulator that can target suppressive regulatory immune cells and meanwhile enhance effector cells. Here, a therapeutic scaffold is engineered based on a fibrin hydrogel to codeliver CTX and anti‐PD‐L1 antibody (aPDL1) for the prevention of cancer recurrence postsurgery. It is demonstrated that the sequential release of CTX and aPDL1 from the fibrin hydrogel can lead to selective depletion of regulatory T cells (Treg) in the residual tumor, which would then synergize the immune checkpoint blockade therapy. The therapeutic benefit is demonstrated in an orthotopic breast tumor and an orthotopic ovarian tumor model after incomplete resection of primary tumors. In this work, the strategy provides a clinically valuable option for preventing cancer recurrence postsurgery.  相似文献   

16.
    
The immune system is composed of immune organs, immune cells, and immunoactive substances, which plays a vital role in antitumor immunity in cancer immunotherapy. During the process of the antitumor immune response, many factors are involved in the cancer immune cycle. Therefore, developing intelligent strategies based on the steps of the cancer immune cycle to elicit the immune responses for enhanced cancer immunotherapy is of great significance. In this review, the key factors in each step of the cancer immune cycle are discussed, and then, the intelligent therapeutic strategies for modulating the immune surveillance against cancer are highlighted. Considering the demand for cancer immunotherapy in clinic, some suggestions for constructing new intelligent strategies are also put forward, which will make antitumor immunity more effective and advance the development of cancer immunotherapy.  相似文献   

17.
    
A novel platform of dendritic nanogels is herein presented, capitalizing on the self‐assembly of allyl‐functional polyesters based on dendritic‐linear‐dendritic amphiphiles followed by simple cross‐linking with complementary monomeric thiols via UV initiated off‐stoichiometric thiol‐ene chemistry. The facile approach enabled multigram creation of allyl reactive nanogel precursors, in the size range of 190–295 nm, being readily available for further modifications to display a number of core functionalities while maintaining the size distribution and characteristics of the master batch. The nanogels are evaluated as carriers of a spread of chemotherapeutics by customizing the core to accommodate each individual cargo. The resulting nanogels are biocompatible, displaying diffusion controlled release of cargo, maintained therapeutic efficacy, and decreased cargo toxic side effects. Finally, the nanogels are found to successfully deliver pharmaceuticals into a 3D pancreatic spheroids tumor model.  相似文献   

18.
目的:探讨乳腺癌患者化疗后性功能状况,分析其原因,探讨应对措施和策略。方法:在患者自愿、主动配合的情况下,对80例乳腺癌患者在化疗前后应用《乳腺癌性功能调查问卷》进行调查,行统计学分析,对其性功能状况进行评估,并进行原因分析。结果:在接受调查的患者中,所有被调查者均认为患病后有不同程度的性功能障碍,并认为与疾病和治疗有关,还有药物、配偶态度和形体改变等因素可能对性功能有影响。结论:化疗对乳腺癌患者性功能有明显影响,针对患者认为的可能影响因素,需要进行一些相对应的干预措施。  相似文献   

19.
    
Immunotherapy has significantly improved cancer treatment, yet the immunosuppressive tumor microenvironment (TME) remains a substantial impediment to therapeutic efficacy. Nanomodulators have emerged as promising tools to address immunosuppressive factors within the TME, enhancing clinical interventions such as immunotherapy, chemotherapy, and radiotherapy while minimizing associated safety risks with immune modulators. In this review, recent advancements are spotlighted in TME-targeted nanomodulators from drug delivery to drug-free concepts. First, nanomodulators designed to synergize with various immunomodulatory agents, including gene tools (mRNA, siRNA, miRNA, plasmid DNA, and CRISPER system), cytokines, immune agonists, and inhibitors are analyzed. Subsequently, recently developed drug-free nanomodulators designed to modulate the physicochemical and biological properties in the microenvironment of solid tumors are succinctly presented. Finally, integrative perspectives on the future development and challenges of nanomodulators in assisting cancer immunotherapy are offered as conclusions.  相似文献   

20.
    
Advances in cancer immunology have revealed that immunological tolerance, which is characterized by low immunogenicity, insufficient antigen presentation, and low T lymphocyte infiltration, increases the expression of inhibitory receptors and cytokines in tumors. These features make it possible for tumor cells to easily escape attack by immune cells. Nanomaterials, with unique properties such as ultrasmall size, unique surface characteristics, and multivalent effects, have attracted an increasing amount of attention in the regulation of the immunological microenvironment of tumors. In this review, the use of functional nanomaterials to reverse immunological tolerance in tumors is examined, including the use of nanomaterials for efficient cancer vaccines, checkpoint blockade delivery, cytokine delivery, artificial antigen presentation cells, and adoptive cell therapy. The benefits and challenges of using nanomaterials to circumvent the immunological tolerance of tumors are also discussed.  相似文献   

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