RESUMEN
Low-expression antigens, especially neoantigens, pose a significant challenge in immunotherapy for low immunogenicity pancreatic cancer. Increasing the tumor mutation burden is crucial to enhance the expression of tumor antigens and improve tumor immunogenicity. However, the incomplete intervention in DNA stability hampers effective elevation of the tumor mutation burden, thus reducing the probability of neoantigen. To address this issue, we have developed a novel nano-regulator that intervenes in the DNA stability of tumor cells, thereby enhancing tumor mutations. This nano-regulator comprises metal-organic frameworks (MOFs) encapsulating DNA damage agent doxorubicin and DNA damage repair inhibitor siRNA-ATR, enabling simultaneous induction of DNA mutations and inhibition of their repair. Importantly, this regulator, named as MOFDOX&siATR, can modulate the tumor gene expression profile, induce the production of neoantigens of Atp8b1, and enhance the immunogenicity of pancreatic cancer. The characteristics of DNA stability intervention by MOFDOX&siATR hold promise for augmenting the immune response in low immunogenic tumors, making it a potential nanomedicine for the treatment of pancreatic cancer.
Asunto(s)
Antígenos de Neoplasias , Daño del ADN , Inmunoterapia , Neoplasias Pancreáticas , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Inmunoterapia/métodos , Antígenos de Neoplasias/inmunología , Humanos , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Estructuras Metalorgánicas/química , ARN Interferente Pequeño , RatonesRESUMEN
The utilization of extracellular vesicles (EV) in immunotherapy, aiming at suppressing peripheral immune cells responsible for inflammation, has demonstrated significant efficacy in treating various inflammatory diseases. However, the clinical application of EV has faced challenges due to their inadequate targeting ability. In addition, most of the circulating EV would be cleared by the liver, resulting in a short biological half-life after systemic administration. Inspired by the natural microvesicles (MV, as a subset of large size EV) are originated and shed from the plasma membrane, we developed the immunosuppressive MV-mimetic (MVM) from endotoxin tolerant dendritic cells (DC) by a straightforward and effective extrusion approach, in which DC surface proteins were inherited for providing the homing ability to the spleen, while αCD3 antibodies were conjugated to the MVM membranes for specific targeting of T cells. The engineered MVM carried a large number of bioactive cargos from the parental cells, which exhibited a remarkable ability to promote the induction of regulatory T cells (Treg) and polarization of anti-inflammatory M2 macrophages. Mechanistically, the elevated Treg level by MVM was mediated due to the upregulation of miR-155-3p. Furthermore, it was observed that systemic and local immunosuppression was induced by MVM in models of sepsis and rheumatoid arthritis through the improvement of Treg and M2 macrophages. These findings reveal a promising cell-free strategy for managing inflammatory responses to infections or tissue injury, thereby maintaining immune homeostasis.
Asunto(s)
Micropartículas Derivadas de Células , Células Dendríticas , Inflamación , Células Dendríticas/efectos de los fármacos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Animales , Ratones , Inflamación/tratamiento farmacológico , Micropartículas Derivadas de Células/metabolismo , Ratones Endogámicos C57BL , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Vesículas Extracelulares , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/inmunología , Sepsis/inmunología , Sepsis/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Humanos , Inmunoterapia/métodosRESUMEN
BACKGROUND: Steroid-induced avascular necrosis of the femoral head (SANFH) is characterized by osteoblast apoptosis, leading to a loss of bone structure and impaired hip joint function. It has been demonstrated that erythropoietin (EPO) performs a number of biological roles. OBJECTIVE: We examined the effects of EPO on SANFH and its regulation of the STAT1-caspase 3 signaling pathway. METHOD: In vitro, osteoblasts were treated with dexamethasone (Dex) or EPO. We identified the cytotoxicity of EPO by CCK-8, the protein expression of P-STAT1, cleaved-caspase9, cleaved-caspase3, Bcl-2, BAX, and cytochrome c by Western blotting, and evaluated the apoptosis of osteoblasts by flow cytometry. In vivo, we analyzed the protective effect of EPO against SANFH by hematoxylin and eosin (H&E), Immunohistochemical staining, and Micro-computed tomography (CT). RESULTS: In vitro, EPO had no apparent toxic effect on osteoblasts. In Dex-stimulated cells, EPO therapy lowered the protein expression of BAX, cytochrome c, p-STAT1, cleaved-caspase9, and cleaved-caspase3 while increasing the expression of Bcl-2. EPO can alleviate the apoptosis induced by Dex. In vivo, EPO can lower the percentage of empty bone lacunae in SANFH rats. CONCLUSION: The present study shows that EPO conferred beneficial effects in rats with SANFH by inhibiting STAT1-caspase 3 signaling, suggesting that EPO may be developed as a treatment for SANFH.
Asunto(s)
Eritropoyetina , Necrosis de la Cabeza Femoral , Ratas , Animales , Caspasa 3/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Necrosis de la Cabeza Femoral/inducido químicamente , Necrosis de la Cabeza Femoral/tratamiento farmacológico , Necrosis de la Cabeza Femoral/metabolismo , Citocromos c/metabolismo , Citocromos c/farmacología , Microtomografía por Rayos X , Apoptosis , Transducción de Señal , Osteoblastos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Eritropoyetina/farmacología , Esteroides/efectos adversosRESUMEN
Currently, tumor immunotherapy is becoming a new revolution in tumor treatment. Generated from tumor cell lysate (TCL) or irradiated tumor cells, the whole tumor antigen-based vaccines have the possibility to enhance antitumor immune response without survival from immune surveillance in personalized immunotherapy. Here, polydopamine nanoparticles (PDA NPs) after self-polymerization are covalently coated with TCL to form PDA@CL. Engineered Salmonella (EnS) wrapped with PDA@CL (EnS@PDA@CL) is targeted the localization of the tumor site by intravenous administration. EnS@PDA@CL delivered autologous antigen-containing nanoparticles to tumor hypoxia regions through blood circulation. The PDA@CL particles promote the maturation of dendritic cells (DCs), thus eliciting the infiltration of whole tumor antigens specific cytotoxic T lymphocytes, significantly triggering antitumor immunity. The tumor regression in the Panc02 mice confirms the therapeutic potential of EnS@PDA@CL in clinical personalized immunotherapy.
Asunto(s)
Vacunas contra el Cáncer , Nanopartículas , Neoplasias , Animales , Ratones , Autoantígenos , Inmunoterapia , Neoplasias/tratamiento farmacológico , Linfocitos T Citotóxicos , Antígenos de Neoplasias , Bacterias , Células DendríticasRESUMEN
BACKGROUND: Ulcerative colitis (UC) is a major type of inflammatory bowel disease (IBD), which could induce bloody stool, diarrhea, colon atrophy and eventually lead to colorectal cancer. The conventional daily oral administration of drugs only relieve the inflammatory response of colon in the short term, Biological agents such as antibody drugs has proven its efficiency in inhibiting colitis, while the low drug bioavailability means that large doses of antibodies are required, ultimately causing systemic toxicity. Small interfering RNA (siRNA) has significant advantages over antibody drugs in terms of safety and efficacy, and it have been widely applied as potential candidates for a variety of inflammation-related diseases. However, oral delivery of siRNA fails to overcome the degradation of the gastrointestinal environment to produce a significant therapeutic effect in ulcerative colitis. Herein, we design the hybrid delivery system that the siRNA loaded MOF encapsulated in the sodium alginate particles to overcome the barriers in the oral process. RESULTS: The hybrid delivery system (SA@MOF-siRNATNFα) was successfully constructed, and it could not only survive the low pH environment in the stomach and small intestine, but also taken up more by inflammatory macrophages, as well as released much more MOF-siRNATNFα. Moreover, SA@MOF-siRNATNFα tended to enriched and infiltrated into local colon tissues. As a result, SA@MOF-siRNATNFα significantly reduced the progression of colitis, of which the treated mice did not experience significant weight loss, bloody stools and diarrhea. CONCLUSION: We confirmed that the formulation of hydrogel-metal-organic framework hybrids could improve the protection of incorporated payload in the gastric and early small intestine, enhancing the delivery of MOF-siRNA to colon.
Asunto(s)
Colitis Ulcerosa , Colitis , Estructuras Metalorgánicas , Animales , Colitis/tratamiento farmacológico , Colitis Ulcerosa/tratamiento farmacológico , Diarrea , Hidrogeles , Ratones , ARN Interferente Pequeño , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Tumor recurrence and metastasis have become thorny problems in clinical tumor therapy. Vaccine-mediated antitumor immune response has emerged as a significant postoperative inhibition for tumor recurrence and metastasis. However, limited tumor antigens are not conducive to trigger complete antigen-specific T cell-mediated immune responses. Herein, the design of a hydrogel vaccine system containing a granulocyte-macrophage colony stimulating factor (GM-CSF), based on surgically removed tumor cell lysates, was reported. The hydrogel was formed by crosslinking tumor cell lysates and alginate at low temperatures. The GM-CSF was released from the hydrogel to recruit dendritic cells (DCs), which provided a completely personalized tumor antigen pool. They were combined to foster the production of powerful antigen-specific T cells. The personalized hydrogel was implanted at the surgical site and it stimulated the antitumor immune response for the inhibition of residual tumor cells. Delightfully, the personalized hydrogel inhibited the tumor recurrence and metastasis well in a post-surgical mice tumor model, in combination with a programmed death-ligand 1 antibody (αPD-L1). The results demonstrated that the development of a personalized hydrogel and a combination of αPD-L1 provided a new strategy to prevent tumor recurrence and metastasis.
Asunto(s)
Vacunas contra el Cáncer , Hidrogeles , Animales , Antígenos de Neoplasias , Vacunas contra el Cáncer/uso terapéutico , Células Dendríticas , Ratones , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/prevención & control , Linfocitos TRESUMEN
Chemotherapy is a traditional treatment method in clinical cancer treatment. However, it is limited due to the large toxic side effects of chemotherapeutics. Nanomedicines have shown great potential in the application of tumor therapy. The size of nanoparticles as a crucial factor in the enhanced permeability and retention (EPR) effect can be regulated for the enhanced chemotherapy. Therefore, we believe that regulation of nanoparticle size can be used as an effective sensitizer to enhance the therapeutic effect of chemotherapy drugs on tumors. Here, we prepared several nanoparticles of different hydrodynamic diameters commonly found in nanomedical applications by the diblock copolymer of methoxy polyethylene glycol-poly (ϵ-caprolactone) (mPEG-PCL). The blood circulation effect and organ distribution in blood were detected by fluorescence labeled nanoparticles. We found that the small-sized nanoparticles exhibited much longer blood circulation time than the large-sized nanoparticles in vivo, and thus the nanoparticle concentration in the tumor tissue was relatively high. Systematic injection of the doxorubicin (DOX) loaded nanoparticles can effectively inhibit tumor growth. Compared to the free drug, tumor cells were much more sensitive to DOX loaded nanoparticles of small size. Our nano-drug delivery system has been proven to be safe and nontoxic in vivo and was suitable for use as a sensitizer in clinical oncology chemotherapy.
Asunto(s)
Doxorrubicina/uso terapéutico , Glioma/tratamiento farmacológico , Nanopartículas/química , Tamaño de la Partícula , Polímeros/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Circulación Sanguínea/efectos de los fármacos , Línea Celular Tumoral , Doxorrubicina/farmacología , Humanos , Ratones Endogámicos NOD , Ratones SCID , Nanopartículas/efectos adversosRESUMEN
Nanocarriers have shown great advantages in increasing the efficiency of drug delivery and reducing drug side effects. However, their lack of targeting and on-demand drug release abilities will seriously limit their clinical application. Herein, we report tumor cell membrane coated nanogels (NGs) with redox/pH dual-responsive behavior for enhanced tumor chemotherapy. The cell membrane coating improves the tumor targeting efficiency, and stimuli-responsive drug release enhances the therapeutic effects. These NGs are well dispersed in PBS with an average size of 109.1 ± 5.2 nm and a narrow polydispersity index of 0.12. Both in vitro and in vivo studies indicate that these NGs can responsively release the therapeutic drug DOX under acidic conditions or high GSH concentrations and effectively inhibit tumor growth. Based on the results, this nanogel shows promise as a platform for tumor-targeted chemotherapy for future clinical translation.
Asunto(s)
Membrana Celular/química , Portadores de Fármacos/química , Nanogeles/química , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/metabolismo , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Liberación de Fármacos , Femenino , Glutatión/química , Concentración de Iones de Hidrógeno , Ratones , Ratones Endogámicos BALB C , Neoplasias/tratamiento farmacológico , Oxidación-ReducciónRESUMEN
In the past two decades, protein drugs have evolved to become the most successful and important strategy in cancer therapy. However, systematical administration of protein drugs may cause serious side effects. In order to prepare a new promising hydrophilic drugs carrier, we constructed a PEGylated hyaluronic acid nanogel (NI-MAHA-PEG nanogel) with hypoxia and enzymatic responsiveness, which can selectively release hydrophilic drugs interleukin-12 (IL-12) on demand in a tumor microenvironment. We observed that release of IL-12 from nanogels by hypoxia-responsive stimulation, nanogels have anti-tumor effects on melanoma. Compared with physiological conditions, the IL-12 release rate has achieved remarkable growth under hypoxic conditions. Similarly, the drug release rate increased significantly with the addition of 500 U ml-1 hyaluronidase. We provide a novel strategy to allow efficient delivery, on-demand release, and enhanced access of proteins to hypoxic tumor regions. The rational design of this nanogels drug delivery system can further explore the use of various drugs to treat many cancers.
Asunto(s)
Ácido Hialurónico/química , Interleucina-12/administración & dosificación , Melanoma Experimental/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Hipoxia de la Célula , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Interleucina-12/química , Interleucina-12/farmacología , Ratones , Nanogeles , Polietilenglicoles/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This paper describes the state and the development of the application of the modern and traditional image segmentation technology in cell slice image segmentation. It includes edge detection, regional segmentation, wavelet transform, fuzzy mathematics, artificial neural networks, morphological image segmentation and so on. At last, the paper summaries that it is difficult to generally segmentate any kind of biological cell slice image automatically because of the complex structure of cell and cell slice image is not even gray distributed. It should be pointed out that general automatic cell slice image segmentation will be achieved only if visual mathematics model corresponding to mammalian vision systems is setup entirely.