RESUMO
BACKGROUND: The combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon. METHODS: Constructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels. RESULTS: The abscopal effect was further amplified in the "cold" tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response. CONCLUSIONS: Bi was used as an artificially implanted anaerobic target to cause a transient "infection" at the tumor, causing the tumor to become locally inflamed and "hot", and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.
Assuntos
Anticorpos Monoclonais , Camundongos Endogâmicos BALB C , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/farmacologia , Linhagem Celular Tumoral , Feminino , Bactérias Anaeróbias/imunologia , Camundongos , Bifidobacterium , Citocinas/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias/radioterapia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Terapia CombinadaRESUMO
Local hypoxia is a common feature of many solid tumors and may lead to unsatisfactory chemotherapy outcomes. Anaerobic bacteria that have an affinity to hypoxic areas can be used to achieve targeted drug delivery in tumor tissues. In this study, we developed a biocompatible bacteria/nanoparticles biohybrid (Bif@DOX-NPs) platform that employs the anaerobic Bifidobacterium infantis (Bif) to deliver adriamycin-loaded bovine serum albumin nanoparticles (DOX-NPs) into breast tumors. The Bif@DOX-NPs retained the targeting ability of B. infantis to hypoxic regions, as well as the cytotoxicity of DOX. The biohybrids were able to actively colonize the hypoxic tumors and significantly increased drug accumulation at the tumor site. The DOX concentration in the tumor masses colonized by Bif@DOX-NPs was 4 times higher than that in the free DOX-treated tumors, which significantly prolonged the median survival of the tumor-bearing mice to 69 days and reduced the toxic side-effects of DOX. Thus, anaerobic bacteria-based biohybrids are a highly promising tool for the targeted treatment of solid tumors with inaccessible hypoxic regions.
Assuntos
Nanopartículas , Neoplasias , Animais , Bactérias , Doxorrubicina , Sistemas de Liberação de Medicamentos , Hipóxia/tratamento farmacológico , Camundongos , Neoplasias/tratamento farmacológicoRESUMO
Recent insights into the molecular and cellular mechanisms underlying cancer development have revealed the tumor microenvironment (TME) immune cells to functionally affect the development and progression of breast cancer. However, insufficient evidence of TME immune modulators limit the clinical application of immunotherapy for advanced and metastatic breast cancers. Intercellular STAT3 activation of immune cells plays a central role in breast cancer TME immunosuppression and distant metastasis. Accumulating evidence suggests that targeting STAT3 and/or in combination with radiotherapy may enhance anti-cancer immune responses and rescue the systemic immunologic microenvironment in breast cancer. Indeed, apart from its oncogenic role in tumor cells, the functions of STAT3 in TME of breast cancer involve multiple types of immunosuppression and is associated with tumor cell metastasis. In this review, we summarize the available information on the functions of STAT3-related immune cells in TME of breast cancer, as well as the specific upstream and downstream targets. Additionally, we provide insights about the potential immunosuppression mechanisms of each type of evaluated immune cells. Video abstract.
Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Progressão da Doença , Imunidade , Leucócitos/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Neoplasias da Mama/terapia , Feminino , Humanos , Microambiente Tumoral/imunologiaRESUMO
OBJECTIVE: To estimate the prognostic efficacy of several systemic hemato-immunological indices for the treatment of cervical cancer as well as to determine whether the systemic hemato-immunological indices are associated with an increased risk of cervical collision cancer. METHODS: A systematic search was conducted to identify studies that evaluated the prognostic impact of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), thrombocyte-to-lymphocyte ratio (TLR), C-reactive protein/albumin ratio (CAR), and systemic immune-inflammation index (SII) in cervical cancer patients. The endpoints were overall survival (OS) or progression-free survival (PFS) and clinicopathologic parameters. A meta-analysis using random-effect models was performed to calculate hazard ratios (HRs) or odds ratios with 95% confidence intervals. RESULTS: Twenty-two retrospective cohort studies involving 9558 patients were included. Our results show that high NLR, PLR, TLR, and CAR indicated poor prognosis for patients with cervical cancer (HRs = 2.46, 1.88, 3.70, and 3.94, respectively; all P ≤ 0.001). Subgroup analysis suggested that the highest NLR and PLR were more precise biomarkers in patients who were diagnosed with FIGO stage I-III cervical cancer after treatment with chemo-radiotherapy. High TLR and high LMR displayed significant prognostic value in late-FIGO stage III-IV cervical cancer (HRs = 4.33 and 2.032, respectively). Additionally, CAR was associated with poor survival in patients with advanced-FIGO stage cervical cancer and larger tumor size. According to the difference of NLR, the younger (43-51 years old) cervical cancer patients had a tendency of increased collision risk. However, cervical cancer patients in the 52-61 years age group were more vulnerable than their respective counterparts using the pooled estimate for PLR. CONCLUSION: Our findings support a prognostic role for elevated CAR and TLR besides that of NLR and PLR in advanced-FIGO stage cervical cancer.
Assuntos
Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/imunologia , Plaquetas/imunologia , Plaquetas/patologia , Estudos de Coortes , Feminino , Humanos , Linfócitos/imunologia , Linfócitos/patologia , Monócitos/imunologia , Monócitos/patologia , Estudos Observacionais como Assunto , Prognóstico , Análise de Regressão , Estudos RetrospectivosRESUMO
The aim of this study was to explore the synergistic anti-tumor effects of cytarabine hyaluronic acid-tyramine (Ara-HA-Tyr) hydrogel conjugates and radiotherapy (RT) in the Lewis lung cancer (LLC) xenograft model, and the mechanisms involved. The radiotherapy sensitization ratio (SER) of 0.5 µg cytarabine (Ara-C) was 1.619 in the LLC cells. Ara-HA-Tyr was prepared by encapsulating Ara-C into hyaluronic acid-tyramine (HA-Tyr) conjugates. The hydrogels were formed through the oxidative coupling of tyramines by hydrogen peroxide (H2O2) and horseradish peroxidase (HRP). Mice engrafted with the LLC cells were given intra-tumoral injections of saline, Ara-C or Ara-HA-Tyr, with or without RT. The combination of Ara-HA-Tyr and RT increased survival compared to free Ara-C and RT (p < 0.05), and prolonged tumor growth delay (TGD). Furthermore, the RT + Ara-HA-Tyr combination therapy significantly reduced 18F-FDG uptake, induced cell cycle arrest at G2/M-phase, increased apoptosis and histone H2AX phosphorylation (γ-H2AX), and decreased the proliferation index (Ki67) in tumor cells compared to either monotherapy. Taken together, Ara-C encapsulated with HA-Tyr effectively sensitized tumor xenografts to RT and showed significantly less systemic toxicity. Graphical abstract In this work, Ara-C encapsulated with hyaluronic acid-tyramine conjugates (HA-Tyr) was prepared and used to investigate its synergistic anti-tumor efficacy by combination with radiotherapy in the Lewis lung cancer xenograft model. The synergistic mechanism may be related to tumor cell cycle redistribution, apoptosis and expression of histone H2AX phosphorylation.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/radioterapia , Citarabina/administração & dosagem , Ácido Hialurônico/administração & dosagem , Hidrogéis/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Animais , Apoptose , Carcinoma Pulmonar de Lewis/metabolismo , Ciclo Celular , Linhagem Celular Tumoral , Terapia Combinada , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Feminino , Histonas/metabolismo , Injeções Intralesionais , Neoplasias Pulmonares/metabolismo , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Conventional chemotherapy is commonly used to treat non-small cell lung cancer (NSCLC) however it increases therapeutic resistance. In contrast, metronomic chemotherapy (MET) is based on frequent drug administration at lower doses, resulting in inhibition of neovascularization and induction of tumor dormancy. This study aims to evaluate the inhibitory effects, adverse events, and potential mechanisms of MET Vinorelbine (NVB) combined with an angiogenesis inhibitor (Endostar). METHODS: Circulating endothelial progenitor cells (CEPs), apoptosis rate, expression of CD31, vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 (HIF-1α) were determined using flow cytometry, western blot analysis, immunofluorescence staining and Enzyme-linked immunosorbent assay (ELISA) analysis. And some animals were also observed using micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) to identify changes by comparing SUVmax values. In addition, white blood cell (WBC) counts and H&E-stained sections of liver, lungs, kidney, and heart were performed in order to monitor toxicity assessments. RESULTS: We found that treatment with MET NVB + Endo was most effective in inhibiting tumor growth, decreasing expression of CD31, VEGF, HIF-1α, and CEPs, and reducing side effects, inducing apoptosis, such as expression of Bcl-2, Bax and caspase-3. Administration with a maximum tolerated dose of NVB combined with Endostar (MTD NVB + Endo) demonstrated similar anti-tumor effects, including changes in glucose metabolism with micro fluorine-18-deoxyglucose PET/computed tomography (18F-FDG PET/CT) imaging, however angiogenesis was not inhibited. Compared with either agent alone, the combination of drugs resulted in better anti-tumor effects. CONCLUSION: These results indicated that MET NVB combined with Endo significantly enhanced anti-tumor and anti-angiogenic responses without overt toxicity in a xenograft model of human lung cancer.
Assuntos
Administração Metronômica , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Endostatinas , Neoplasias Pulmonares/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Vinorelbina , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Pulmonar de Lewis , Carcinoma Pulmonar de Células não Pequenas/irrigação sanguínea , Linhagem Celular Tumoral , Endostatinas/administração & dosagem , Endostatinas/efeitos adversos , Humanos , Neoplasias Pulmonares/irrigação sanguínea , Camundongos , Vinorelbina/administração & dosagem , Vinorelbina/efeitos adversos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The study aims at investigating the ecological environment Adiantum reniforme var. sinense of in Three Gorges Reservoir region, and providing a reference basis for the protection of resources and artificial cultivation of A. reniforme var. sinense. By using the method of investigation, field survey and experimental analysis, the vegetation, natural geographical environment, climate, soil nutrients of A. reniforme var. sinense were studied and analyzed. The survey found that A. reniforme var. sinense distribution area reduced fast in Three Gorges region, a lot of distribution has diminished and vanished due to excessive digging, currently only in 3 towns of Wanzhou there exist 4 wild distribution areas. The growth of A. reniforme var. sinense needs an environment with low altitude, steep slope and thin soil, northeast slope, canopy height and warm and humid climate characteristics, and the soil in distribution has the characteristics of high organic matter, available nitrogen, available potassium, and low available phosphorus content.
Assuntos
Adiantum/crescimento & desenvolvimento , Dispersão Vegetal , China , Clima , Nitrogênio , Fósforo , Plantas Medicinais/crescimento & desenvolvimento , Potássio , Solo/químicaRESUMO
Non-small cell lung cancer (NSCLC) is the most common cancer worldwide and is a leading cause of lung cancer mortality due to early stage metastases. Cancer stem-like cells (CSLCs) or tumor-initiating cells (TICs) are rare subpopulation cells that are responsible for maintaining tumor growth and invasion leading to recurrence and metastasis. Previous studies revealed that miR-183 can mediate the invasiveness and growth of NSCLC. However, the exact role of miR-183 in regulating the biological behavior of CSLCs in NSCLC remains unclear. In the present study, we explored the regulation of protein tyrosine phosphatase non-receptor type 4 (PTPN4) by miR-183 in vitro using luciferase reporter assays, and we further analyzed the effects of miR-183 on the invasiveness of CSLCs in vitro and in vivo using transwell and bioluminescence assays. Following our finding that miR-183 binds to PTPN4 messenger RNA (mRNA) to prevent its translation through the 3'-untranslated region (UTR), we found that overexpression of miR-183 in CSLCs decreased PTPN4 protein levels while inhibition of miR-183 increased PTPN4 protein levels. The suppression of PTPN4 levels in CSLCs by miR-183 paralleled with a significant promotion in their motility in vitro and in vivo, while anti-sense miR-183 increased PTPN4 levels in CSLCs, which paralleled with a significant decrease in their invasiveness. Furthermore, correlation analysis between miR-183 and PTPN4 in clinical samples demonstrated a statistically significant inverse correlation between PTPN4 mRNA levels and miR-183. In brief, our data indicate that miR-183 plays a pro-invasive role by inverse regulation of PTPN4, and this axis may be a new therapeutic target for suppressing the metastatic capability of CSLCs in NSCLC.
Assuntos
Adenocarcinoma/patologia , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Pulmonares/patologia , MicroRNAs/genética , Invasividade Neoplásica/genética , Proteína Tirosina Fosfatase não Receptora Tipo 4/biossíntese , Antígeno AC133 , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Animais , Western Blotting , Linhagem Celular Tumoral , Movimento Celular , Molécula de Adesão da Célula Epitelial , Citometria de Fluxo , Imunofluorescência , Xenoenxertos , Humanos , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
BACKGROUND: An increasing number of studies have demonstrated the critical role of microRNAs in the pathogenesis of cardiac hypertrophy and dysfunction. This study evaluated whether miR-214 plays a pivotal role in the development of cardiac hypertrophy and heart failure. METHODS: In human tissues, miR-214 overexpression was determined to promote cardiac hypertrophy. We predicted miR-214 direct target by bioinformatics database and verifed it using luciferase dual reporting system. We silenced miR-214 using a specific antagomir in a pressure-overload mouse model of heart failure. RESULTS: Analysis of transgenic mice with cardiomyocyte-specific overexpression of miR-214 indicated that their hearts were 21% heavier than wild-type hearts and expressed several biochemical and functional markers consistent with dilated cardiomyopathy. These findings include enlarged left ventricular internal diameters, wall thinning, reduced ejection fraction, fractional shortening, and an increased fetal gene expression. The enhancer of zeste homolog 2 (EZH2) was confirmed as a direct target of miR-214 in cardiomyocytes. In vivo silencing of miR-214 using a specific antagomir rescued cardiac EZH2 expression and prevented cardiac hypertrophy and dysfunction. CONCLUSIONS: Taken together, these results suggest that miR-214 may induce pathologic cardiac hypertrophy in part by reducing EZH2 messenger RNA levels. MiR-214 may therefore be a potential therapeutic target for treating certain cardiac disease states.
Assuntos
Cardiomegalia/genética , Insuficiência Cardíaca/genética , MicroRNAs/fisiologia , Complexo Repressor Polycomb 2/genética , Animais , Cardiomegalia/diagnóstico por imagem , Proteína Potenciadora do Homólogo 2 de Zeste , Expressão Gênica/fisiologia , Células HEK293 , Insuficiência Cardíaca/diagnóstico por imagem , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Luciferases/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/fisiologia , RNA Mensageiro/genética , Ultrassonografia , Disfunção Ventricular/diagnóstico por imagem , Disfunção Ventricular/genéticaRESUMO
The aim of this study is to compare the contents of five types of anthraquinones which mainly includes chrysophanol, physcion, emodin, rhein and physcion and phenolic acids in ten different processed products from Rheum officinale, and to investigate the effect of different initial processing method on the contents of anthraquinones and phenolic acids. Principal component analysis (PCA) was carried out by SPSS software to evaluate the quality of different processed products from Rh. officinale. In conclusion, the contents of anthraquinones in different processed products from Rh. officinale assume the certain regularity. Whether fresh-cut Rheum officinale Bail and how to dry it are derectly effect the contents of anthraquinones and phenolic compounds. The content of anthraquinones in rheum officinale of drying is obviously higher than smudging, and was more abundant in branch root than tap roots. Rh. officinale of drying which growed in Fengjie gained the highest score in PCA. Meanwhile, the procedure of wetting also help to increase the content of anthraquinones and decrease the content of phenolic acids.
Assuntos
Antraquinonas/química , Química Farmacêutica/métodos , Medicamentos de Ervas Chinesas/química , Hidroxibenzoatos/química , Rheum/químicaRESUMO
OBJECTIVE: To study on the pharmacognostical characteristics of cultivated Fritillaria taipaiensis for providing basis for further development and research. METHODS: Botanical, macroscopic and microscopic identifications, and determination of the content of extract, total saponins and total alkaloids were carried out. RESULTS: Because of various growing years, cultivated Fritillaria taipaiensis had diffferent properties,in addition to tip slightly resembling songbei's tip "embracing the moon", there were greatly different characteristics in the rest of specifications comparing with the traditional Fritillaria cirrhosa. Some were shallow conical or cylindrical, some had slightly rough surface,and some bases were constricted, bitter in taste. There were great differences in its extract and total alkaloids con-tent,and no obvious differences in the content of total saponins. CONCLUSION: The experimental results show that the extract,total saponins and total alkaloids content are not positively correlated or relevant with the current classification of Fritillariae Cirrhosae Bulbus. To consider the medicinal appearance diameter and length, the grade classification should be based on different application requirements, and combined with the evaluation of active ingredients.
Assuntos
Alcaloides/análise , Fritillaria/anatomia & histologia , Fritillaria/química , Plantas Medicinais/química , Saponinas/análise , Medicamentos de Ervas Chinesas/química , Fritillaria/classificação , Farmacognosia , Raízes de Plantas/anatomia & histologia , Raízes de Plantas/química , Plantas Medicinais/anatomia & histologia , Controle de Qualidade , Especificidade da Espécie , Espectrofotometria UltravioletaRESUMO
Immune checkpoint inhibitor (ICI) therapies, such as those blocking the interaction of PD-1 with its ligands, can restore the immune-killing function of T cells. However, ICI therapy is clinically beneficial in only a small number of patients, and it is difficult to predict post-treatment outcomes, thereby limiting its widespread clinical use. Research suggests that gut microbiota can regulate the host immune system and affect cancer progression and treatment. Moreover, the effectiveness of immunotherapy is related to the composition of the patient's gut microbiota; different gut microbial strains can either activate or inhibit the immune response. However, the importance of the microbial composition within the tumor has not been explored until recently. This study describes recent advances in the crosstalk between microbes in tumors and gut microbiota, which can modulate the tumor microbiome by directly translocating into the tumor and altering the tumor microenvironment. This study focused on the potential manipulation of the tumor and gut microbiota using fecal microbiota transplantation (FMT), probiotics, antimicrobials, prebiotics, and postbiotics to enrich immune-boosting bacteria while decreasing unfavorable bacteria to proactively improve the efficacy of ICI treatments. In addition, the use of genetic technologies and nanomaterials to modify microorganisms can largely optimize tumor immunotherapy and advance personalized and precise cancer treatment.
Assuntos
Microbioma Gastrointestinal , Microbiota , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Clonagem Molecular , Neoplasias/terapia , Microambiente TumoralRESUMO
Breast cancer is the second leading cause of cancer-related deaths among women worldwide. Despite significant advancements in chemotherapy, its effectiveness is often limited by poor drug distribution and systemic toxicity caused by the weak targeting ability of conventional therapeutic agents. The hypoxic tumor microenvironment (TME) also plays a vital role in treatment outcomes. Oral anticancer therapeutic agents have gained popularity and show promising results due to their ease of repeated administration. This study introduces autopilot biohybrids (Bif@BDC-NPs) for the effective delivery of doxorubicin (DOX) to the tumor site. This hybrid combines albumin-encapsulated DOX nanoparticles (BD-NPs) coated with chitosan (CS) for breast cancer chemotherapy, along with anaerobic Bifidobacterium infantis (B. infantis, Bif) serving as self-propelled motors. Due to Bif's specific anaerobic properties, Bif@BDC-NPs precisely anchor hypoxic regions of tumor tissue and significantly increase drug accumulation at the tumor site, thereby promoting tumor cell death. In an in-situ mouse breast cancer model, Bif@BDC-NPs achieved 94 % tumor inhibition, significantly prolonging the median survival of mice to 62 days, and reducing the toxic side effects of DOX. Therefore, the new bacteria-driven oral drug delivery system, Bif@BDC-NPs, overcomes multiple physiological barriers and holds great potential for the precise treatment of solid tumors.
Assuntos
Neoplasias da Mama , Quitosana , Doxorrubicina , Nanopartículas , Quitosana/química , Doxorrubicina/farmacologia , Doxorrubicina/química , Doxorrubicina/administração & dosagem , Animais , Feminino , Nanopartículas/química , Camundongos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Administração Oral , Humanos , Portadores de Fármacos/química , Linhagem Celular Tumoral , Microambiente Tumoral/efeitos dos fármacos , Sistemas de Liberação de MedicamentosRESUMO
Malignant ascites is a common complication of advanced cancers, which reduces survival rates and diminishes patients' quality of life. Intraperitoneal chemotherapy is a conventional method for treating cancer-related ascites, but the poor drug retention of conventional drugs requires frequent administration to maintain sustained anti-tumor effects. In this study, we encapsulated doxorubicin (DOX) into Brucea javanica oil (BJO) to develop a water-in-oil (W/O) nanoemulsion called BJO@DOX for the treatment of malignant ascites through in-situ intraperitoneal administration. BJO significantly induced apoptosis of S180 cells by upregulating the expression of p53 and caspase-3 (cleaved). Additionally, BJO notably downregulated the expression of Bcl-2, further promoting apoptosis of S180 cells. Cell apoptosis significantly inhibited ascites formation and tumor cell proliferation in a mouse model. The combination of DOX and BJO exhibited satisfactory synergistic effects, consequently prolonging the survival period of mice. Histological examination of major organs indicated that the nanoemulsion had excellent biosafety in vivo. The BJO@DOX nanoemulsion represents a promising platform for in-situ chemotherapy of malignant ascites.
Assuntos
Apoptose , Ascite , Brucea , Doxorrubicina , Emulsões , Nanopartículas , Óleos de Plantas , Animais , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Ascite/tratamento farmacológico , Brucea/química , Camundongos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Nanopartículas/química , Óleos de Plantas/administração & dosagem , Óleos de Plantas/farmacologia , Óleos de Plantas/química , Injeções Intraperitoneais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Masculino , Proliferação de Células/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
Purpose: The present study aimed to develop a lipid nanoplatform, denoted as "BAL-PTX-LN", co-loaded with chiral baicalin derivatives (BAL) and paclitaxel (PTX) to promote the anti-lung cancer efficacy of paclitaxel and reduce the toxicity of chemotherapeutic drugs. Methods: BAL-PTX-LN was optimized through central composite design based on a single-factor experiments. BAL-PTX-LN was evaluated by TEM, particle size, encapsulation efficiency, hemolysis rate, release kinetics and stability. And was evaluated by pharmacokinetics and the antitumor efficacy studied both in vitro and in vivo. The in vivo safety profile of the formulation was assessed using hematoxylin and eosin (HE) staining. Results: BAL-PTX-LN exhibited spherical morphology with a particle size of 134.36 ± 3.18 nm, PDI of 0.24 ± 0.02, and with an encapsulation efficiency exceeding 90%, BAL-PTX-LN remained stable after 180 days storage. In vitro release studies revealed a zero-order kinetic model of PTX from the liposomal formulation. No hemolysis was observed in the preparation group. Pharmacokinetic analysis of PTX in the BAL-PTX-LN group revealed an approximately three-fold higher bioavailability and twice longer t1/2 compared to the bulk drug group. Furthermore, the IC50 of BAL-PTX-LN decreased by 2.35 times (13.48 µg/mL vs 31.722 µg/mL) and the apoptosis rate increased by 1.82 times (29.38% vs 16.13%) at 24 h compared to the PTX group. In tumor-bearing nude mice, the BAL-PTX-LN formulation exhibited a two-fold higher tumor inhibition rate compared to the PTX group (62.83% vs 29.95%), accompanied by a ten-fold decrease in Ki67 expression (4.26% vs 45.88%). Interestingly, HE staining revealed no pathological changes in tissues from the BAL-PTX-LN group, whereas tissues from the PTX group exhibited pathological changes and tumor cell infiltration. Conclusion: BAL-PTX-LN improves the therapeutic effect of poorly soluble chemotherapeutic drugs on lung cancer, which is anticipated to emerge as a viable therapeutic agent for lung cancer in clinical applications.
Assuntos
Neoplasias Pulmonares , Paclitaxel , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Paclitaxel/administração & dosagem , Animais , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Humanos , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/farmacocinética , Flavonoides/administração & dosagem , Tamanho da Partícula , Nanopartículas/química , Camundongos , Lipossomos/química , Lipossomos/farmacocinética , Células A549 , Lipídeos/química , Masculino , Camundongos Endogâmicos BALB C , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Camundongos Nus , Hemólise/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/administração & dosagemRESUMO
BACKGROUND: Strategies that restore the immune system's ability to recognize malignant cells have yielded clinical benefits but only in some patients. Tumor cells survive cryotherapy and produce a vast amount of antigens to trigger innate and adaptive responses. However, because tumor cells have developed immune escape mechanisms, cryotherapy alone may not be enough to induce a significant immune response. METHODS: The mice were randomly divided into four groups: Group A: low-dose total body irradiation combined with cryotherapy (L-TBI+cryo); Group B: cryotherapy (cryo); Group C: low-dose total body irradiation(L-TBI); Group D: control group (Control). The tumor growth, recurrence, and survival time of mice in each group were compared and the effects of different treatments on systemic anti-tumor immunity were explored. RESULTS: L-TBI in conjunction with cryotherapy can effectively control tumor regrowth, inhibit tumor lung metastasis, extend the survival time of mice, and stimulate a long-term protective anti-tumor immune response to resist the re-challenge of tumor cells. The anti-tumor mechanism of this combination therapy may be related to the stimulation of inflammatory factors IFN-γ and IL-2, as well as an increase in immune effector cells (CD8+ T cells) and a decrease in immunosuppressive cells (MDSC, Treg cells) in the spleen or tumor tissue. CONCLUSIONS: We present unique treatment options for enhancing the immune response caused by cryotherapy, pointing to the way forward for cancer treatment.
Assuntos
Neoplasias Pulmonares , Irradiação Corporal Total , Camundongos , Animais , Crioterapia , Terapia Combinada , Imunidade , Linfócitos T CD8-Positivos , Neoplasias Pulmonares/secundárioRESUMO
There has been a great amount of advancement in the early field of nano-immunotherapy and combination therapy. Persistent consideration regarding the clinical challenges and therapeutic hindrance should be tended to achieve therapeutic efficacy and potential. In this review, we will address how nanotechnology could defeat the difficulties resulting from cancer immunotherapy, how nanoparticles' utilization can enhance the efficacy of immune checkpoint blockers, and reconstituting the tumor microenvironment can promote antitumor responses. Moreover, this review discusses how nanoparticles mediate therapeutic modalities like chemotherapy, photodynamic therapy, photothermal therapy, and radiotherapy, which are used to target and destroy cancerous cells, initiate the release of tumor antigens, and can trigger anti-tumor immunity reactions. Furthermore, we analyzed the potential benefits of immunotherapy combinatorial using the nanoparticle delivery system to prevent tumor recurrence, hinder metastases, and decrease systemic toxicity of major organs and healthy cells common with uncontrolled targeting.
Assuntos
Imunoterapia , Nanotecnologia , Neoplasias , Humanos , Neoplasias/tratamento farmacológicoRESUMO
Immunostimulatory effects of radiotherapy can be synergistically augmented with immune checkpoint blockade to act both on irradiated tumor lesions and distant, non-irradiated tumor sites. Our hypothesis was that low-dose total body irradiation (L-TBI) combined with hypo-fractionated radiotherapy (H-RT) and anti-programmed cell death protein 1 (aPD-1) checkpoint blockade would enhance the systemic immune response. We tested the efficacy of this triple therapy (L-TBI + H-RT + aPD-1) in BALB/c mice with bilateral breast cancer xenografts. The L-TBI dose was 0.1 Gy. The primary tumor was treated with H-RT (8 Gy × 3). The PD-1 monoclonal antibody was injected intraperitoneally, and the secondary tumors not receiving H-RT were monitored for response. The triple therapy significantly delayed both primary and secondary tumor growths, improved survival rates, and reduced the number of lung metastasis lesions. It increased the activated dendritic and CD8+ T cell populations and reduced the infiltration of myeloid-derived suppressor cells in the secondary tumor microenvironment relative to other groups. Thus, L-TBI could be a potential therapeutic modality, and when combined with H-RT and aPD-1, the therapeutic effect could be enhanced significantly.
Assuntos
Neoplasias , Irradiação Corporal Total , Animais , Camundongos , Humanos , Receptor de Morte Celular Programada 1 , Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos , Imunidade , Morte Celular , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológicoRESUMO
Background: Considering the strong attenuation of photons and the potential to increase the deposition of radiation, high-atomic number nanomaterials are often used as radiosensitizers in cancer radiotherapy, of which gold nanoparticles (GNPs) are widely used. Materials and Methods: We prepared albumin-modified GNPs (Alb-GNPs) and observed their radiosensitizing effects and biotoxicity in human non-small-cell lung carcinoma tumor-bearing mice models. Results: The prepared nanoparticles (Alb-GNPs) demonstrated excellent colloidal stability and biocompatibility at the mean size of 205.06 ± 1.03 nm. Furthermore, clone formation experiments revealed that Alb-GNPs exerted excellent radiosensitization, with a sensitization enhancement ratio (SER) of 1.432, which is higher than X-ray alone. Our in vitro and in vivo data suggested that Alb-GNPs enabled favorable accumulation in tumors, and the combination of Alb-GNPs and radiotherapy exhibited a relatively greater radiosensitizing effect and anti-tumor activity. In addition, no toxicity or abnormal irritating response resulted from the application of Alb-GNPs. Conclusion: Alb-GNPs can be used as an effective radiosensitizer to improve the efficacy of radiotherapy with minimal damage to healthy tissues.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas Metálicas , Radiossensibilizantes , Animais , Humanos , Camundongos , Ouro/farmacologia , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/radioterapia , Radiossensibilizantes/farmacologia , AlbuminasRESUMO
Introduction: Zinc finger and SCAN domain-containing protein 18 (ZSCAN18) has been investigated as a putative biomarker of multiple human cancers. However, the expression profile, epigenetic modification, prognostic value, transcription regulation, and molecular mechanism of ZSCAN18 in breast cancer (BC) remain unknown. Methods: In the study, we present an integrated analysis of ZSCAN18 in BC based on public omics datasets with the use of multiple bioinformatics tools. Genes potentially regulated through restoration of ZSCAN18 expression in MDA-MB-231 cells were investigated to identify pathways associated with BC. Results: We observed that ZSCAN18 was downregulated in BC and mRNA expression was significantly correlated with clinicopathological parameters. Low expression of ZSCAN18 was found in the HER2-positive and TNBC subtypes. High expression of ZSCAN18 was associated with good prognosis. As compared to normal tissues, the extent of ZSCAN18 DNA methylation was greater with fewer genetic alterations in BC tissues. ZSCAN18 was identified as a transcription factor that might be involved in intracellular molecular and metabolic processes. Low ZSCAN18 expression was associated with the cell cycle and glycolysis signaling pathway. Overexpression of ZSCAN18 inhibited mRNA expression of genes associated with the Wnt/ß-catenin and glycolysis signaling pathways, including CTNNB1, BCL9, TSC1, and PFKP. ZSCAN18 expression was negatively correlated with infiltrating B cells and dendritic cells (DCs), as determined by the TIMER web server and reference to the TISIDB. ZSCAN18 DNA methylation was positively correlated with activated B cells, activated CD8+ and CD4+ T cells, macrophages, neutrophils, and activated DCs. Moreover, five ZSCAN18-related hub genes (KDM6B, KAT6A, KMT2D, KDM1A, and HSPBP1) were identified. ZSCAN18, ZNF396, and PGBD1 were identified as components of a physical complex. Conclusion: ZSCAN18 is a potential tumor suppressor in BC, as expression is modified by DNA methylation and associated with patient survival. In addition, ZSCAN18 plays important roles in transcription regulation, the glycolysis signaling pathway, and the tumor immune microenvironment.